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Heavy metals

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  • 1. TRAINING FOR HEALTH CARE PROVIDERS [Date …Place …Event…Sponsor…Organizer] Event… Sponsor… ADVERSE HEALTH EFFECTS OF HEAVY METALS IN CHILDREN Childrens Health and the Environment WHO Training Package for the Health Sector World Health Organization www.who.int/ceh October 2011 1<<NOTE TO USER: Please add details of the date, time, place and sponsorship of the meetingfor which you are using this presentation in the space indicated.>><<NOTE TO USER: This is a large set of slides from which the presenter should select themost relevant ones to use in a specific presentation. These slides cover many facets of theproblem. Present only those slides that apply most directly to the local situation in theregion. Please replace the examples, data, pictures and case studies with ones that arerelevant to your situation.>><<NOTE TO USER: This slide set discusses routes of exposure, adverse health effects andcase studies from environmental exposure to heavy metals, other than lead and mercury,please go to the modules on lead and mercury for more information on those. Please refer toother modules (e.g. water, neurodevelopment, biomonitoring, environmental anddevelopmental origins of disease) for complementary information>>
  • 2. Children and heavy metals LEARNING OBJECTIVES To define the spectrum of heavy metals (others than lead and mercury) with adverse effects on human health To describe the epidemiology of adverse effects of heavy metals (Arsenic, Cadmium, Copper and Thallium) in children To describe sources and routes of exposure of children to those heavy metals To understand the mechanism and illustrate the clinical effects of heavy metals’ toxicity To discuss the strategy of prevention of heavy metals’ adverse effects 2The scope of this module is to provide an overview of the public health impact, adversehealth effects, epidemiology, mechanism of action and prevention of heavy metals (otherthan lead and mercury) toxicity in children.
  • 3. Children and heavy metals WHY HEAVY METALS? WHO 10 chemicals of major public health concern including heavy metals including Air pollution Arsenic Asbestos Benzene Cadmium Dioxin and dioxin-like substances Inadequate or excess fluoride Lead Mercury Highly hazardous pesticides 3 Chemicals are part of our daily life. All living and inanimate matter is made up of chemicals and virtually every manufactured product involves the use of chemicals. Many chemicals can, when properly used, significantly contribute to the improvement of our quality of life, health and well-being. But other chemicals are highly hazardous and can negatively affect our health and environment when improperly managed. WHO compiled a list of the 10 major chemicals of concern, which includes many heavy metals: •Air pollution •Arsenic •Asbestos •Benzene •Cadmium •Dioxin and dioxin-like substances •Inadequate or excess fluoride •Lead •Mercury •Highly hazardous pesticides Notes from: •WHO 10 chemicals of major public health concern. Available at www.who.int/ipcs/features/10chemicals_en.pdf – accessed 22 September 2011.3
  • 4. Children and heavy metals PERIODIC TABLE – BY GROUPS OF ELEMENTS Light Metals Heavy Metals Nonmetals Inert gases www.webelements.com 4The “periodic table” or Mendeleev’s table, organizes chemical elements according to their atomic number, electron configurationand valence numbers. This table illustrates the groups of elements.The main heavy metals are listed below, with their atomic numbers, symbols and names:4 - Beryllium (Be)13 - Aluminum (Al)24 - Chrome (Cr)25 - Manganese (Mn)26 - Iron (Fe)27 - Cobalt (Co)28 - Nickel (Ni)29 - Copper (Cu)30 - Zinc (Zn)33 - Arsenic (As)34 - Selenium (Se)42 - Molybdenum (Mo)47 - Silver (Ag)48 - Cadmium (Ca)50 - Tin (Sn)51 - Antimony (Sb)56 - Barium (Ba)80 - Mercury (Hg)81 - Thallium (Ti)82 - Lead (Plumbum, Pb)Motivations for controlling heavy metal concentrations in gas streams are diverse. Some of them are dangerous to health or to theenvironment (e.g. Hg, Cd, As, Pb, Cr), some may cause corrosion (e.g. Zn, Pb), some are harmful in other ways (e.g. arsenic maypollute catalysts). Within the European community, the 13 elements of highest concern are As, Cd, Co, Cr, Cu, Hg, Mn, Ni, Pb, Sn,and Ti, the emissions of which are regulated in waste incinerators. Some of these elements are actually necessary for humans inminute amounts (Co, Cu, Cr, Ni) while others are carcinogenic or toxic, affecting, among others, the central nervous system (Hg,Pb, As), the kidneys or liver (Hg, Pb, Cd, Cu) or skin, bones, or teeth (Ni, Cd, Cu, Cr).[3]Heavy metal pollution can arise from many sources but most commonly arises from the purification of metals, e.g., the smelting ofcopper and the preparation of nuclear fuels. Electroplating is the primary source of chromium and cadmium. Through precipitationof their compounds or by ion exchange into soils and mud, heavy metal pollutants can localize and lay dormant. Unlike organicpollutants, heavy metals do not decay and thus pose a different kind of challenge for remediation. Currently, plants ormicroorganisms are tentatively used to remove some heavy metals such as mercury. Plants which exhibit hyper accumulation canbe used to remove heavy metals from soils by concentrating them in their bio matter. Some treatment of mining tailings hasoccurred where the vegetation is then incinerated to recover the heavy metals.In medical usage, heavy metals are loosely defined and include all toxic metals irrespective of their atomic weight: "heavy metalpoisoning" can possibly include excessive amounts of iron, manganese, aluminum, mercury, or beryllium (the fourth lightestelement) or such a semimetal as arsenic. This definition excludes bismuth, the heaviest of approximately stable elements, becauseof its low toxicity.Refs:•Malkoç S et al. Street dust pollution of some metals along Eskisehir urban roads, Turkey. Available atbildiri.anadolu.edu.tr/papers/bildirimakale/3492_b353n54.pdf – accessed 22 September 2011•Zevenhoven, Kilpinen. Trace elements. Alkali metals. 2001. 8-27Image from www.webelements.com – used with copyright permission
  • 5. Children and heavy metals DEFINITIONS OF HEAVY METAL: A PARTIAL LIST Definitions in terms of density (SG=specific gravity) metals fall naturally into 2 groups: light metals (densities < 4) and heavy metals (densities >7) (Bjerrum, 1936) metal having a SG.4 (Van Nostrand, 1964) metal of high SG, especially a metal having a SG of 5.0 or greater (Merriam, 1976) metal with a density >5 (Brewer, 1983) metal with a density >6 g/cm3 (Davies, 1987) metal of sg > 4 (Grant, 1987) metal with a density of 5.0 or greater (Flexner, 1987) metal with a density >4.5 g/cm3 (Streit, 1994) metal with a density >3.5-5 g/cm3 (Falbe, 1996) element with a density >6 g/cm3 (Thornton, 1995) Dufus J, 2002 5In medicine, heavy metals are often not well defined and include all toxic metals (including lighter ones): "heavymetal poisoning" can possibly include excessive amounts of iron, manganese, aluminum, mercury,or beryllium (the fourth lightest element) or such a semimetal as arsenic. This definition excludes bismuth, theheaviest of approximately stable elements, because of its low toxicity.There are various definitions used for heavy metals. Many are based on specific gravity. This slide states severalof these definitions.Refs:•Bennet H (ed). Concise Chemical and Technical Dictionary, 4th enlarged ed. Edward Arnold, London. 1986.•Bjerrum N. Bjerrums Inorganic Chemistry, 3rd Danish ed. Heinemann, London. 1936.•Brewer M, Scott T (eds). Concise Encyclopedia of Biochemistry. Walter de Gruyter, Berlin, New York. 1983.•Davies BE. Consequences of environmental contamination by lead mining in Wales. Hydrobiologia. 1987, 49:213.•Falbe J, Regitz M (eds). Roempp Chemie-Lexikon. George Thieme, Weinheim. 1996.•Flexner SB (ed). The Random House Dictionary of the English Language, 2nd ed. Random House, New York.1987.•Grant R, Grant C (eds). Grant and Hackhs Chemical Dictionary. McGraw-Hill, New York. 1987.•Holister G, Porteous A (Eds.). The Environment: A Dictionary of the World Around Us. Arrow, London, 1976.•Lewis RJ Sr. (ed). Hawleys Condensed Chemical Dictionary, 12th ed. Van Nostrand Reinhold, New York. 1993.•Merriam. 3rd New International Dictionary. Merriam, Chicago. 1976.•Streit B. Lexikon der Okotoxikologie. VCH, Weinheim. 1994.•Thornton I. Metals in the Global Environment: Facts and Misconceptions. International Council on Metals and theEnvironment, Ottawa. 1995.•US Environmental Protection Agency (EPA). EPAs Terms of Environment. U.S. Environmental ProtectionAgency. 2000.•Van Nostrand R. Van Nostrand International Encyclopedia of Chemical Science. Van Nostrand, New Jersey.1964.Tables based on Duffus J. Heavy metals: a meaningless term. Pure Appl. Chem. 2002. 74,5:793–807.
  • 6. Children and heavy metals DEFINITIONS OF HEAVY METAL: A PARTIAL LIST Definitions in terms of atomic weight (mass) metal with high atomic weight (Holister, 1976) metal of atomic weight > sodium (Bennet, 1986) metal of atomic weight greater than sodium (Brewer, 1983) that forms soaps on reaction with fatty acids (Lewis, 1993) metallic element with high atomic weight (e.g., mercury, chromium, cadmium, arsenic, and lead); can damage living things at low concentrations and tend to accumulate in the food chain (EPA, 2000) metallic element with an atomic weight > 40 Dufus J, 2002 6Other ways to define heavy metals are based on atomic weight. This slide shows examples of these definitions.Refs:•Bennet H (ed). Concise Chemical and Technical Dictionary, 4th enlarged ed. Edward Arnold, London. 1986.•Bjerrum N. Bjerrums Inorganic Chemistry, 3rd Danish ed. Heinemann, London. 1936.•Brewer M, Scott T (eds). Concise Encyclopedia of Biochemistry. Walter de Gruyter, Berlin, New York. 1983.•Davies BE. Consequences of environmental contamination by lead mining in Wales. Hydrobiologia. 1987, 49:213.•Falbe J, Regitz M (eds). Roempp Chemie-Lexikon. George Thieme, Weinheim. 1996.•Flexner SB (ed). The Random House Dictionary of the English Language, 2nd ed. Random House, New York.1987.•Grant R, Grant C (eds). Grant and Hackhs Chemical Dictionary. McGraw-Hill, New York. 1987.•Holister G, Porteous A (Eds.). The Environment: A Dictionary of the World Around Us. Arrow, London, 1976.•Lewis RJ Sr. (ed). Hawleys Condensed Chemical Dictionary, 12th ed. Van Nostrand Reinhold, New York. 1993.•Merriam. 3rd New International Dictionary. Merriam, Chicago. 1976.•Streit B. Lexikon der Okotoxikologie. VCH, Weinheim. 1994.•Thornton I. Metals in the Global Environment: Facts and Misconceptions. International Council on Metals and theEnvironment, Ottawa. 1995.•US Environmental Protection Agency (EPA). EPAs Terms of Environment. U.S. Environmental ProtectionAgency. 2000.•Van Nostrand R. Van Nostrand International Encyclopedia of Chemical Science. Van Nostrand, New Jersey.1964.Tables based on Duffus J. Heavy metals: a meaningless term. Pure Appl. Chem. 2002. 74,5:793–807.
  • 7. Children and heavy metals PHYSIOLOGICAL ROLES OF HEAVY METALS IN HUMANS Iron – hemoglobin, myoglobin Cobalt – coenzyme Copper – co-factor in enzymes Zinc – in enzymes Selenium – in enzymes Chromium – Cr3+ in enzymes 7Some heavy metals have essential roles for human health. Listed in this slide are several examples of healthattributes of heavy metals, including:•Copper – is an integral part of numerous enzymes including ferro-oxidase (ceruloplasmin), cytochrome – c –oxidase, superoxide dismutase and others. It plays a role in iron metabolism, melanin synthesis and centralnervous system function The adult body contains 50-120 mg of copper. High concentrations are found in liver,brain, heart, spleen and kidneys.•Selenium – is a component of the enzyme glutathione peroxidase, which protects protein, cell membranes, lipidsand nucleic acids from oxidant molecules.•Chromium – potentiates the action of insulin in patients with impaired glucose tolerance. The suggested intake(in adults) is 50-200 micrograms/day.Some of these elements are necessary for humans in minute amounts (Co, Cu, Cr, Ni), while others arecarcinogenic or toxic, affecting, among others, the central nervous system (Hg, Pb, As), the kidneys or liver (Hg,Pb, Cd, Cu) or skin, bones, or teeth (Ni, Cd, Cu, Cr).Heavy metal pollution can arise from many sources but often arises from metal purification processes, such as thesmelting of copper and the preparation of nuclear fuels. Electroplating is the primary source of chromiumand cadmium. Through precipitation of their compounds or by ion exchange into soils and mud, heavy metalpollutants can localize and lay dormant. Unlike organic pollutants, heavy metals do not decay and thus pose adifferent kind of challenge for remediation. Currently, plants or microorganisms are tentatively used to removesome heavy metals such as mercury. Plants which exhibit hyper accumulation can be used to remove heavymetals from soils by concentrating them in their bio matter. Some treatment of mining tailings has occurred wherethe vegetation is then incinerated to recover the heavy metals.Ref:•Duffus J. Heavy metals: a meaningless term. Pure Appl. Chem. 2002. 74,5:793–807.•Harrison’s principles of Internal Medicine, 15th edition. McGraw-Hill, 2001.•Hogan CM. Heavy metal. Encyclopedia of Earth. National Council for Science and the Environment. EdsMonosson E, Cleveland C. Washington DC. 2010.
  • 8. Children and heavy metals HISTORICAL AND CURRENT USE OF HEAVY METALS AS REMEDIES Historical use - obsolete Current use Aluminum – anti acids Arsenic – treatment against: protozoa, Gold – rheumatoid arthritis helminthes, ameba, Iron – anemia syphilis, spirochetes Zinc – food supplement Copper – emetic Selenium – food supplement Arsenic – leukemia and homeopathic medications 8•Gold injections have been used to treat rheumatoid arthritis since the 1930s. The injectionsare given each week at first, although the frequency may be decreased as the gold becomeseffective. Gold injections can be continued for life if they are helpful. Side-effects can occur,affecting the blood and the kidneys, and regular blood and urine tests are used to check forany abnormalities. Skin irritation may sometimes occur. Gold tablets were introduced at onepoint but are very rarely used because they are not as effective as the injections.•Arsenic trioxide was approved by the US Food and Drug Administration as an orphan drugfor the secondary treatment of acute promyelocytic leukemiaRefs:•Arthritis Research Campaign. UK. Available at www.arc.org – accessed June 2010•Kosnett MJ et al. Critical Care Toxicology. Diagnosis and Management of the CriticallyPoisoned Patient. Elsevier Mosby. 2005.
  • 9. Children and heavy metals SELECTED HEAVY METALS AND ISSUES 1. Arsenic 2. Cadmium 3. Copper 4. Thallium 5. Controversies about issues associated with exposure to heavy metals 9This slide lists the heavy metals and related issues discussed in this module.<<NOTE TO USER: Please change this slide if you are only presenting selectedcomponents of this library of slides.>>
  • 10. Children and heavy metals SELECTED HEAVY METALS ARSENIC 10Elemental arsenic is a naturally-occurring silver-gray solid metalloid. The element (zerovalence) form, which rarely exists in nature and has low solubility, is seldom a cause ofhuman toxicity. The other forms of arsenic and their toxicity are discussed in the followingslides.Ref:•Kosnett MJ et al. Critical Care Toxicology. Diagnosis and Management of the CriticallyPoisoned Patient. Elsevier Mosby. 2005.
  • 11. Children and heavy metals SOURCES OF ARSENIC • Geological: rocks, soil, water (well-water) • Industrial: - By-product of smelting for copper, lead, zinc - 62,000 tons emitted annually from smelting (Bissen, 2003) - Burning fossil fuel - Manufacture of pesticides - Wood preservatives • Total emissions to air in 1990 in the European Community: 575 tons (Jarup L, 2003) 11Main sources of arsenic include:<<READ SLIDE>>Refs:•Bissen M, Frimmel FH. Arsenic – a review. Part 1: Occurrence, Toxicity, Speciation,Mobility. Acta Hydrochim Hydrobiol. 2003, 31: 9-18.•European Commission General-DirectoratesEnvironment. Ambient air pollution by As, Cdand Ni compounds. Position paper, Final version, October 2000. Brussels: EuropeanCommission General-DirectoratesEnvironment. 2000.•Jarup L. Hazards of heavy metal contamination. British Medical Bulletin. 2003. 68:167-182.
  • 12. Children and heavy metals ARSENIC - CURRENT USES • Use is dropping because of toxicity • Wood preservative (phased out in US in 2003) • Silicon-based computer chips • Manufacturing of glass • Feed additive (poultry and swine) • Drugs (for leukemia) WHO • Homeopathic medications may contain arsenic • Arsenic pesticides 12In 2009 the Center for Food Safety (CFS) and the Institute for Agriculture and Trade Policy (IATP) filed a petition with the Food and Drug Administration(FDA) calling for the immediate withdrawal of approvals for all animal drug applications for arsenic-containing compounds used in animal feed. Theseadditives are commonly used in poultry production to induce faster weight gain and create the appearance of a healthy color in meat from chickens,turkeys and hogs. The petition was supported by a coalition of food and farm groups around the country.Arsenic-containing compounds have been approved additives to animal feed since the 1940s and are currently used in chicken, turkey and swineproduction. Most arsenic-containing animal feed additives are not used to treat sickness. Instead, arsenicals are generally approved for "increasedweight gain, improved feed efficiency, and improved pigmentation. The European Union has never approved the use of arsenicals in animal feed,acknowledging the lack of science supporting health or safety standards for such use.In 2009 U.S. Representative Steve Israel of New York announced legislation calling for a ban on the use of the arsenical compound roxarsone in poultryfeed. His bill, the "Poison-Free Poultry Act of 2009," would prohibit all uses of roxarsone as a food additive in poultry. The groups applauded the bill, butmaintained that it did not go far enough. Their petition not only calls for a ban on roxarsone, but also on Arsanilic acid, Nitarsone, and Carbarsone,commonly used compounds which contain arsenicals.Arsenic-treated wood is the result of a chemical process in which wood is treated with a pesticide/preservative called chromated copper arsenate (CCA)to prevent rotting in lumber designed for outdoor use. Chromated copper arsenate contains arsenic, chromium, and copper and was widely used forresidential purposes in the US from the 1970s until the US Environmental Protection Agency phased it out in 2003.Ref:•Institute for Agriculture and Trade Policy (IATP). Available at www.iatp.org/documents/fda-petition-on-arsenic - accessed 22 September 2011.Chromated copper arsenate-treated wood can be hazardous to human health because arsenic is classified as a known carcinogen. Exposure to arseniccan cause cancer of the lung, bladder, skin, kidney, prostate, and nasal passage. Data released in November 2003 by the US Environmental ProtectionAgency show that 90 percent of children repeatedly exposed to arsenic-treated wood face a greater than one-in-one million risk of cancer. One-in-onemillion is the US Environmental Protection Agencys historic threshold of concern about the carcinogenic effects of toxic chemicals. Arsenic exposure canalso lead to nerve damage, dizziness, and numbness. Arsenic has been linked to immune diseases, cardiovascular disease, diabetes, and changes inhormone function. Lung and bladder cancer are the two health effects most often related to exposure to chromated copper arsenate-treated wood.Chromated copper arsenate-treated wood can be found virtually anywhere outdoor lumber is being utilized. Due to the increased risk to children, theuses currently receiving the most attention are play sets, decks, and picnic tables. Arsenic can leach to the surface of the treated wood, becomingaccessible for absorption through exposed hands and skin touching the wood surface and, especially in the case of children, ingestion through normalhand-to-mouth behavior. The arsenic can also leach into the ground surrounding the location of the treated wood, providing yet another exposurepathway for children playing in the area.In March 2003, US Environmental Protection Agency finalized a voluntary agreement with preservative manufacturers to ban the production ofchromated copper arsenate-treated wood for most residential uses as of December 31, 2003. However, the ban does not prohibit the sale of chromatedcopper arsenate-treated wood produced prior to December 31, 2003, nor does the measure address existing structures. With regard to retail sales, awarning label must be displayed in locations where chromated copper arsenate-treated wood is sold. The US Environmental Protection Agency has alsoremoved chromated copper arsenate from its list of approved chemical pesticides.The Consumer Product Safety Commission (CPSC) is also involved in the regulation of arsenic-treated wood. The Consumer Product SafetyCommission has officially stated that there is an increased lifetime risk of developing lung or bladder cancer from exposure to arsenic for the individualwho plays on chromated copper arsenate-treated wood play sets during early childhood. However, in November 2003, Consumer Product SafetyCommission declined to ban the use of chromated copper arsenate-treated wood in playground equipment, citing the US Environmental ProtectionAgency -industry voluntary agreement to phase out the manufacture of chromated copper arsenate-treated wood.Arsenic Trioxide was approved by the US Food and Drug Administrationas an orphan drug for the secondary treatment of acute promyelocytic leukemia.Refs:•Ellenhorn MJ, Barceloux DG. Arsenic in medical toxicology: diagnosis and treatment of human poisoning. New York: Elsevier. 1988: 1012-6.•Kosnett MJ et al. Critical Care Toxicology. Diagnosis and Management of the Critically Poisoned Patient. Elsevier Mosby. 2005.•National Center for Healthy Housing. Available at www.nchh.org/Home.aspx - accessed 22 September 2011Picture: WHO
  • 13. Children and heavy metals ARSENIC - HUMAN EXPOSURE • Average 20 ug/day from food and water Country Sample Total As/day • Background air is < 0.1 ug/m3 Australia Adult male 73 ug • Drinking water, usually < 5 ug/L 2 year old 17 ug • Food, usually < 10 ug/day Canada Adult male 59 ug 1-4 years old 15 ug WHO guideline value of arsenic in water = 0.01mg/L or 10 ppb USA adults 53 ug 0.5-2 years 28 ug Estimated average daily intake old 13This slide presents the source of arsenic exposure in three countries.<<READ SLIDE>>Refs:•WHO. Arsenic and Arsenic Compounds. Environmental Health Criteria. InternationalProgramme on Chemical Safety, WHO Geneva. 2001.•WHO. Guidelines for drinking-water quality, fourth edition. WHO. 2011.
  • 14. Children and heavy metals PARENTAL SMOKING: ADDITIONAL SOURCE FOR ARSENIC EXPOSURE IN CHILDREN Parental smoking Mean arsenic in Urine arsenic children’s urine (Ug/gr/cr) concentration in children according Not smoking 4.2 to the smoking status of the parents One parent smokes 5.5 Bulletin WHO, 1992 Two parents smoke 13 14This slide presents data on prenatal arsenic exposure in relation to parental smoking.Ref:•Chiba M, Masironi R. Toxic and trace elements in tobacco and tobacco smoke. Bull WorldHealth Organ. 1992, 70(2):269-75.While the harmful health effects of carbon monoxide, nicotine, tar, irritants and other noxiousgases that are present in tobacco smoke are well known, those due to heavy metals andother toxic mineral elements in tobacco smoke are not sufficiently emphasized. Tobaccosmoking influences the concentrations of several elements in some organs. This reviewsummarizes the known effects of some trace elements and other biochemically importantelements (Al, As, Cd, Cr, Cu, Pb, Mn, Hg, Ni, Po-210, Se, and Zn) which are linked withsmoking. Cigarette smoking may be a substantial source of intake of these hazardouselements not only to the smoker but also, through passive smoking, to nonsmokers. Theadverse health effects of these toxic elements on the fetus through maternal smoking, andon infants through parental smoking, are of special concern.
  • 15. Children and heavy metals CHEMICAL COMPOSITION AND TOXICITY: ARSINE GAS (AsH3) THE MOST TOXIC Inorganic arsenic Organic arsenic Trivalent (As3+) Less soluble Arsenic trioxide Less toxic Soluble More toxic Produced by bio-methylation Pentavalent (As5+) Detoxified in humans Arsenic pentoxide e.g. Lead arsenate - High source: shrimp Lower solubility Less toxic 15The toxicity of arsenic depends on its chemical composition and valency, arsine gas beingthe most toxic form.Please note the information on this slide comes mostly from adult exposure data.Ref:•Ellenhorn MJ, Barceloux DG. Arsenic in medical toxicology: diagnosis and treatment ofhuman poisoning. New York: Elsevier. 1988: 1012-6.
  • 16. Children and heavy metals ARSINE GAS The most toxic, a potent hemolytic agent Colorless Non-irritant Evolves from arsenic compounds by addition of acid Immediate death occurs at 150 ppm, or in 30 minutes from 25-50 ppm 16Hemolysis from arsine inhalation may result in intra-renal deposition of hemoglobin and debris of lysederythrocytes leading to renal tubular damage and renal failure, as well as hypoxia.Refs:•Ellenhorn MJ. Barceloux DG. Arsenic in medical toxicology: diagnosis and treatment of humanpoisoning. New York: Elsevier. 1988: 1012-6.•Kosnett MJ. Arsenic. In: Brent J et al. Critical Care Toxicology. Diagnosis and Management of theCritically Poisoned Patient. Elsevier Mosby, 2005.
  • 17. Children and heavy metals ARSENIC - ABSORPTION Inorganic arsenic (As3+) 80-90% absorbed from intestine Organic arsenic (seafood) poorly absorbed from intestine - considered not toxic in children Arsine gas – by inhalation Skin - As3+ high absorption (lipid soluble) 17This slide and the following 3 slides describe the toxicokinetics of arsenic in the body, at fourstages, using the acronym ADME:A - AbsorptionD - DistributionM - MetabolismE - Excretion<<READ SLIDE>>Ref:•American Academy of Pediatrics Committee on Environmental Health. Arsenic. In: EtzelRA, Balk SJ eds. Pediatric Environmental Health. 2nd Edition. Elk Grove Village, IL:American Acadermy of Pediatrics. 2003: 87-98.
  • 18. Children and heavy metals ARSENIC - DISTRIBUTION Bound to red blood cells and globulin Re –distribution (24 hours): liver, lungs, spleen Binds to sulfhydryl-containing proteins Long term distribution and high concentration in bone and keratinized tissues Hair and fingernails (Mees’ lines) WHO 18Distribution of arsenic, once absorbed, in the human tissues is uneven, with higher affinityand higher concentrations in some tissues.Note: Mees lines are white bands traversing the nail.
  • 19. Children and heavy metals ARSENIC - METABOLISM As5+ (Arsenate) As3+ (Arsenite) Methyl arsenite (in liver) Dimethyl arsenite (readily eliminated – urine) Institute of Neurotoxicology and Neurological Disorders 19Arsenic undergoes transformation in the body from the pentavalent (As5+), less toxic form,which is well absorbed, to the trivalent (As3+), more toxic form.Ref:•Ellenhorn MJ, Barceloux DG. Arsenic in medical toxicology: diagnosis and treatment ofhuman poisoning. New York: Elsevier. 1988: 1012-6.Figure kindly provided by Steven G. Gilbert, PhD, DABT. Credit: The Institute ofNeurotoxicology and Neurological Disorders / Toxipedia. Used with permission. Available atwww.toxipedia.org – further educational resources available atwww.toxipedia.org/display/toxipedia/Teaching+Resources
  • 20. Children and heavy metals ARSENIC - MECHANISM OF TOXICITY Induces Reactive Oxygen Species (ROS) and oxidative stress Binds to thiols Alters signal cascade Causes imbalance in antioxidant levels Triggers apoptosis Cell death 20The slide shows the mechanism of toxicity of arsenic: the main effect is through induction ofoxidative stress and impairment of the antioxidant defense mechanism, leading to apoptosisand cell death.Ref:•Flora SJ, Mittal M, Mehta A. Heavy metal induced oxidative stress and its possible reversalby chelation therapy. Indian J Med Res. 2008. 128(4):501-23.
  • 21. Children and heavy metals ARSENIC – EXCRETION 3-5 days (mainly by kidneys) Breast milk – very low arsenic levels Crosses placenta, may cause stillbirth WHO 21Arsenic is excreted mainly by the kidneys. Renal tubules can convert As5+ (Arsenate) to themore toxic As3+ (Arsenite).Prenatal exposure to arsenic, through placental transfer, can cause marked damage to thefetusRef:•Ellenhorn MJ, Barceloux DG. Arsenic in medical toxicology: diagnosis and treatment ofhuman poisoning. New York: Elsevier. 1988: 1012-6.
  • 22. Children and heavy metals ARSENIC - ACUTE - TOXICITY Arsine gas (AsH3) – Immediate death at 150 ppm Inorganic arsenic (arsenic trioxide) 70-180 mg can be fatal (2 mg/kg in a child) Constriction of the throat, difficulty in swallowing Garlic taste, severe thirst Severe intestinal pain, vomiting, diarrhea Muscle cramps Cardiac arrhythmias (torsade de pointes, ventricular fibrillation) Coma and death 22Acute arsenic toxicity has multi-organ system manifestations: gastrointestinal, muscular,cardiac and neurological symptoms.<<READ SLIDE>>
  • 23. Children and heavy metals PEDIATRIC ARSENIC INGESTION CASE Pediatric case of acute arsenic ingestion treated initially with dimercaprol (BAL) and D-penicillamine (DP), and later with dimercaptosuccinic acid (DMSA) 22-month-old girl ingested 1 oz 2.27% sodium arsenate. Immediate vomiting and diarrhea. Presented with a blood pressure of 96/72 mm Hg, pulse 160 beats/min, respirations 22 breaths/min. Pale and lethargic. Cullen et al, 1995 23•Acute arsenic toxicity is rare, with no pediatric cases of acute arsenic poisoning in the recent literature. We reporta pediatric case of acute arsenic ingestion treated initially with dimercaprol (BAL) and D-penicillamine (DP), andlater with dimercaptosuccinic acid (DMSA).•A 22-month-old girl ingested 1 oz 2.27% sodium arsenate and developed immediate vomiting and diarrhea. Thepatient presented with a blood pressure of 96/72 mm Hg, pulse 160 beats/min, respirations 22 breaths/min. Shewas pale and lethargic.•Gastric lavage was performed, and abdominal X-ray was normal. She continued to have gastrointestinalsymptoms and received 3 mg/kg BAL. She had sinus tachycardia up to 200 beats/min. In 12 hours, she wasasymptomatic and was started on oral DP. On day one, 24-hour urine arsenic was 4,880 micrograms/L.•She remained asymptomatic and was discharged on day 6 on oral DP. She did well except for a rash that couldhave been a side effect of DP. DMSA was given for 4 days.•The excretion half-life was 2.5 days, faster than the spontaneous excretion half-life expected in adults.Ref:•Cullen NM et al. Pediatric arsenic ingestion. Am J Emerg Med. 1995. 13(4):432-5.
  • 24. Children and heavy metals PEDIATRIC ARSENIC INGESTION CASE Gastric lavage performed, abdominal X-ray was normal. Continued to have gastrointestinal symptoms and received 3 mg/kg dimercaprol (BAL). Sinus tachycardia up to 200 beats/min. In 12 hours, asymptomatic and was started on oral D-penicillamine (DP). On day 1, 24-hour urine arsenic was 4,880 micrograms/L. Remained asymptomatic and was discharged on day 6 on oral D-penicillamine (DP). She did well except for a rash that could have been a side effect of D-penicillamine (DP). Dimercaptosuccinic acid (DMSA) was given for 4 days. The excretion half-life was 2.5 days, faster than the spontaneous excretion half- life expected in adults. Cullen et al, 1995 24•Acute arsenic toxicity is rare, with no pediatric cases of acute arsenic poisoning in the recent literature. We reporta pediatric case of acute arsenic ingestion treated initially with dimercaprol (BAL) and D-penicillamine (DP), andlater with dimercaptosuccinic acid (DMSA).•A 22-month-old girl ingested 1 oz 2.27% sodium arsenate and developed immediate vomiting and diarrhea. Thepatient presented with a blood pressure of 96/72 mm Hg, pulse 160 beats/min, respirations 22 breaths/min. Shewas pale and lethargic.•Gastric lavage was performed, and abdominal X-ray was normal. She continued to have gastrointestinalsymptoms and received 3 mg/kg BAL. She had sinus tachycardia up to 200 beats/min. In 12 hours, she wasasymptomatic and was started on oral DP. On day one, 24-hour urine arsenic was 4,880 micrograms/L.•She remained asymptomatic and was discharged on day 6 on oral DP. She did well except for a rash that couldhave been a side effect of DP. DMSA was given for 4 days.•The excretion half-life was 2.5 days, faster than the spontaneous excretion half-life expected in adults.Ref:•Cullen NM et al. Pediatric arsenic ingestion. Am J Emerg Med. 1995. 13(4):432-5.
  • 25. Children and heavy metals SURVIVAL AFTER A MASSIVE OVERDOSE OF ARSENIC TRIOXIDE An 18-year-old man deliberately ingested termiticide with a massive dose of arsenic trioxide Arsenic concentration 6.3 micromol/L in serum, and 253 micromol/L in the first 24-hour urine sample, with a urinary arsenic/creatinine ratio of 84 200 micromol/mol Treated with dimercaptosuccinic acid (DMSA), replaced by dimercaprol on days 2-5, and required intensive support for multisystem organ failure, but recovered slowly 9 weeks after the ingestion the only ongoing clinical issue was persistent but slowly improving peripheral neuropathy Kim LH & Abel SJ, 2009 25•An 18-year-old man deliberately ingested termiticide with a massive dose of arsenictrioxide. Arsenic concentration was 6.3 micromol/L in serum, and 253 micromol/L in the first24-hour urine sample, with a urinary arsenic/creatinine ratio of 84 200 micromol/mol.•He was treated with the chelating agent dimercaptosuccinic acid (DMSA), replaced bydimercaprol on days 2-5, and required intensive support for multisystem organ failure, butrecovered slowly.•Nine weeks after the ingestion the only ongoing clinical issue was persistent but slowlyimproving peripheral neuropathy.Ref:•Kim LH, Abel SJ. Survival after a massive overdose of arsenic trioxide. Crit CareResusc. 2009, 11(1):42-5.
  • 26. Children and heavy metals ARSENIC - CHRONIC TOXICITY Main source: drinking water Clinical manifestations: • Garlic odor on breath • Excessive perspiration • Muscle tenderness and weakness • Changes in skin pigmentation • Paresthesia in hands and feet • Peripheral vascular disease WHO • Gangrene of feet – Black foot disease • Cancer (skin, kidney, bladder) The Institute of Neurotoxicology and Neurological Disorders26Arsenicosis is the effect of arsenic poisoning, usually over a long period such as from 5 to 20 years.Drinking arsenic-rich water over a long period results in various health effects including skin problems(such as colour changes on the skin, and hard patches on the palms and soles of the feet), skincancer, cancers of the bladder, kidney and lung, and diseases of the blood vessels of the legs andfeet, and possibly also diabetes, high blood pressure and reproductive disorders.Absorption of arsenic through the skin is minimal and thus hand-washing, bathing, laundry, etc. withwater containing arsenic do not pose human health risks.In China (Province of Taiwan) exposure to arsenic via drinking-water has been shown to cause asevere disease of the blood vessels, which leads to gangrene, known as ‘black foot disease’. Thisdisease has not been observed in other parts of the world, and it is possible that malnutritioncontributes to its development. However, studies in several countries have demonstrated that arseniccauses other, less severe forms of peripheral vascular disease.Chronic arsenic toxicity occurred as a large epidemic in Bangladesh as shown in the next slides.Refs:•Smith AH, Lingas EO, Rahman M. Contamination of drinking-water by arsenic in Bangladesh: a publichealth emergency. Bulletin of the World Health Organization, 2000, 78 (9).•WHO. Water-related diseases. Available atwww.who.int/water_sanitation_health/diseases/arsenicosis/en/ - accessed 22 September 2011Slide kindly provided by Steven G. Gilbert, PhD, DABT. Used with permission. Credit: The Institute ofNeurotoxicology and Neurological Disorders / Toxipedia. Available at www.toxipedia.org – furthereducational resources available at www.toxipedia.org/display/toxipedia/Teaching+ResourcesImage: Skin lesions from arsenic poisoning. From Smith AH, Lingas EO, Rahman M. Contamination ofdrinking-water by arsenic in Bangladesh: a public health emergency. Bulletin of the World HealthOrganization, 2000, 78 (9).
  • 27. Children and heavy metals ARSENIC CONTAMINATION IS A GROWING PROBLEM THROUGHOUT THE WORLD Argentina, Chile, China, India, Mexico, United States, Vietnam, Thailand and Bangladesh Worst cases in Bangladesh and West Bengal regions 27Natural arsenic contamination is a cause for concern in many countries of the world includingArgentina, Bangladesh, Chile, China, India, Mexico, Thailand and the United States of America. Casereports on the situation in various countries have been compiled and the arsenic problem inBangladesh in particular has prompted more intensive monitoring in many other countries.Note: The yellow and darker areas in the maps at the bottom of the slide mark the areas with higherarsenic concentrations in water.Refs:•Smith AH, Lingas EO, Rahman M. Contamination of drinking-water by arsenic in Bangladesh: a publichealth emergency. Bulletin of the World Health Organization, 2000, 78 (9).•WHO. Water-related diseases. Available atwww.who.int/water_sanitation_health/diseases/arsenicosis/en/ - accessed 22 September 2011.Millions of children are exposed to excessive amounts of fluoride through drinking water contaminatedfrom natural geological sources. In China, the burning of fluoride-rich coal adds to the problem. Smallamounts of fluoride are good for teeth; it is added to toothpaste and, in some countries, to drinkingwater. At higher doses, it destroys teeth and accumulates in bones, leading to crippling skeletaldamage. With their bodies still growing, children are most at risk. Like fluoride, arsenic is widelydistributed throughout the earths crust, and is present in almost all waters in very small amounts. Incertain areas, however, there are dangerous levels of this toxin in children’s drinking water. The mosttragic example is Bangladesh, where thousands of wells are causing a mass poisoning of thepopulation. Unsafe wells are marked with red paint, warning people that this water is not for drinking.Image and notes from Gordon B et al. Inheriting the world, the Atlas on Childrens Health and theEnvironment. WHO, Myriad Editions Ltd, 2004.
  • 28. Children and heavy metals US WATER ARSENIC MAP http://co.water.usgs.gov/trace/arsenic 28Note: The various colours indicate different concentrations of arsenic in water, with red beingthe highest.Ref:•U.S. Geological Survey (USGS) . Map of US – arsenic in water – Available athttp://co.water.usgs.gov/trace/arsenic/ - accessed 22 September 2011.
  • 29. Children and heavy metals BANGLADESH WATER ARSENIC MAP Peter Ravenscroft Arsenic crisis information center bicn.com/acic 29Image: Arsenic in West Bengal & Bangladesh – Arsenic Crisis Information Center. Availableat http://bicn.com/acic – accessed 22 September 2011. Credit: Peter Ravenscroft. Used withcopyright permission.Note: The various colours indicate different probabilities of high concentrations of arsenic inwater, with violet being the highest.
  • 30. Children and heavy metals ARSENIC - BANGLADESH EPIDEMIC Problem originated in the 1970s UNICEF program to provide “safe” water Arsenic wasn’t a known pollutant at the time Saved thousands of lives from microbial pathogens, but … 35 to 77 million citizens at risk of arsenic poisoning (out of a population of 125 million) Bangladesh wells range from 0 to 1,660 ppb (WHO guideline value of arsenic in water: 10 ppb) 30The Bangladesh arsenic epidemic is considered one of the largest toxicological events in the modernera, affecting a huge proportion of the population, as described in this slide.<<READ SLIDE>>Ref:•Smith AH, Lingas EO, Rahman M. Contamination of drinking-water by arsenic in Bangladesh: a publichealth emergency. Bulletin of the World Health Organization, 2000, 78 (9).The contamination of groundwater by arsenic in Bangladesh is the largest poisoning of a population inhistory, with millions of people exposed. This paper describes the history of the discovery of arsenic indrinking-water in Bangladesh and recommends intervention strategies. Tube-wells were installed toprovide ‘‘pure water’’ to prevent morbidity and mortality from gastrointestinal disease. The water fromthe millions of tube-wells that were installed was not tested for arsenic contamination. Studies in othercountries where the population has had long-term exposure to arsenic in groundwater indicate that 1in 10 people who drink water containing 500 mg of arsenic per litre may ultimately die from cancerscaused by arsenic, including lung, bladder and skin cancers. The rapid allocation of funding andprompt expansion of current interventions to address this contamination should be facilitated. Thefundamental intervention is the identification and provision of arsenic-free drinking water. Arsenic israpidly excreted in urine, and for early or mild cases, no specific treatment is required. Communityeducation and participation are essential to ensure that interventions are successful; these should becoupled with follow-up monitoring to confirm that exposure has ended. Taken together with thediscovery of arsenic in groundwater in other countries, the experience in Bangladesh shows thatgroundwater sources throughout the world that are used for drinking-water should be tested forarsenic.•WHO. Guidelines for drinking-water quality, fourth edition. WHO. 2011.
  • 31. Children and heavy metals ARSENIC - BANGLADESH EPIDEMIC Tube well options: Shallow well Deep well Deep Concerns Renewability Contamination from drilling? 31Ref:•Smith AH, Lingas EO, Rahman M. Contamination of drinking-water by arsenic inBangladesh: a public health emergency. Bulletin of the World Health Organization, 2000, 78(9).Tube-wells have been used in Bangladesh since the 1940s. However, the problem ofarsenic-contaminated water has only recently come to light due to the increasing number oftube-wells used over the past 20 years and the subsequent increase in the number ofindividuals drinking from them. Historically, surface water sources in Bangladesh have beencontaminated with microorganisms, causing a significant burden of disease and mortality.Infants and children suffered from acute gastrointestinal disease resulting from bacterialcontamination of stagnant pond water. Consequently, during the 1970s the United NationsChildren’s Fund (UNICEF) workedwith the Department of Public Health Engineering to installtube-wells to provide what was presumably a safe source of drinking-water for thepopulation. These wells consist of tubes that are 5 cm in diameter that are inserted into theground at depths of usually less than 200 m. The tubes are then capped with a cast iron orsteel hand pump. At the time the wells were installed, arsenic was not recognized as aproblem in water supplies, and therefore standard water testing procedures did not includetests for arsenic. During the 1980s, UNICEF’s support for installing tube-wells decreasedbecause the private sector was able to supply and install millions more of them. By 1997,UNICEF indicated in its country report for Bangladesh that it had surpassed its goal ofproviding 80% of the population by 2000 with access to ‘‘safe’’ drinking-water in the form oftube-wells, ring-wells and taps. Presently, three out of four tube-wells in Bangladesh areprivately owned.
  • 32. Children and heavy metals ARSENIC - HEALTH RISKS Arsenic poisoning appears after 10 years of consumption as arsenicosis Can lead to: • Keratosis • Gangrene • Cancer: skin, kidney, bladder, lung N. Karim, NGO: Earth Identity Project, Bangladesh 32This slide includes the main manifestations of chronic arsenic toxicity.<<READ SLIDE>>Photographs by Nasrine Karim, NGO: Earth Identity Project, Bangladesh. Hands and feet"before" from an arsenicosis patient. Used with permission.
  • 33. Children and heavy metals ARSENIC - HEALTH RISKS Young children may develop arsenicosis Cancers appear after 20 years Huge epidemic expected in the near future WHO 33<<READ SLIDE>>Image: Children near a tube-well disconnected due to contamination of water with arsenic.From Smith AH, Lingas EO, Rahman M. Contamination of drinking-water by arsenic inBangladesh: a public health emergency. Bulletin of the World Health Organization, 2000, 78(9).
  • 34. Children and heavy metals WORLD BANK ARSENIC PUBLIC HEALTH PROJECT Duration: 2002 – 2006 Components: 1. Public education 2. Provider education 3. Epidemiological research 4. Case management 34The Arsenic Mitigation - Water Supply Project for Bangladesh reduces mortality andmorbidity in rural and urban populations caused by arsenic contamination of the countrysgroundwater. The project aims to significantly reduce the quantity of arsenic ingested;increase access to a sustainable safe water supply; and increase the percentage of treatedarsenicosis patients in the project areas. There are three components. The first, on-sitemitigation, 1) provides technical assistance, training, and logistical support to build capacityand operate the project management unit (PMU); 2) implements community interventions bydeveloping a community-based organization capable of supplying short-term, alternativewater supply/sanitation infrastructure; 3) prepares and implements a technical and financialproposal; and 4) audits, evaluates, and monitors project impact and groundwater quality. Thesecond component strengthens the PMUs capacity to collect, manage, and evaluate data forwater quality, arsenic contamination, and socioeconomic conditions; undertakes wellscreening and community education; and funds studies and research on participatoryplanning, implementing appropriate technology, cost recovery, appropriate technology fortesting and treating arsenic in groundwater, and land use/arsenic interactions. The thirdcomponent, institutional strengthening, builds capacity in arsenic mitigation and participatorywater supply and sanitation.Notes fromweb.worldbank.org/external/projects/main?pagePK=64283627&piPK=64290415&theSitePK=40941&menuPK=228424&Projectid=P050745 – accessed 22 September 2011.
  • 35. Children and heavy metals BANGLADESH ARSENIC MITIGATION WATER SUPPLY PROJECT STATUS - MITIGATION Offered where > 40% tube-wells affected Community chooses: Deep tube-well (in coastal areas) Dug well Pond sand filter Rainwater harvesting Removal technologies on experimental basis (to be expanded after verification) All sub-districts completed mid 2002 WHO 35The Arsenic Mitigation - Water Supply Project for Bangladesh World Bank Project.The lessons learned included: A) Arsenic mitigation needs to be mainstreamed into thewater supply sector in order to be sustainable, focusing on innovative ways to deliver safewater supply in both non-piped and piped water supply; B) Decentralized community-basedplanning and management of rural water supply and sanitation with a central role for localgovernments has been demonstrated as a model for future interventions by the Governmentof Bangladesh; C) Supply of bacteriologically safe water should be the priority, not justarsenic-safe water; and D) The rolling out of pilot village piped water supply with significantprivate financing and management through carefully controlled and guided assistance fromboth the PMU and the Bank is a good example of field-testing and development of large-scale investments.Notes from www-wds.worldbank.org/external/default/main?pagePK=64193027&piPK=64187937&theSitePK=523679&menuPK=64187510&searchMenuPK=64187283&siteName=WDS&entityID=000020953_20070724113908– accessed 22 September 2011.Picture: WHO /Henrietta Allen. Bangladesh.
  • 36. Children and heavy metals ARSENIC - REDUCING EXPOSURE Avoid (e.g. do not use treated lumber) Test drinking water Stop smoking Wash hands National monitoring arsenic in poultry The Institute of Neurotoxicology and Neurological Disorders 36<<READ SLIDE>>Slide kindly provided by Steven G. Gilbert, PhD, DABT. Used with permission. Credit: TheInstitute of Neurotoxicology and Neurological Disorders / Toxipedia. Available atwww.toxipedia.org – further educational resources available atwww.toxipedia.org/display/toxipedia/Teaching+Resources
  • 37. Children and heavy metals HEALTH EFFECTS OF EARLY LIFE EXPOSURE TO ARSENIC Inorganic arsenic is a potent human carcinogen and general toxicant > 100 million people are exposed to elevated levels, mainly via drinking water, but also via industrial emissions Arsenic is metabolized via methylation and reduction reactions Main metabolites excreted in urine Inorganic arsenic and its methylated metabolites easily pass the placenta Vahter M, 2008 37<<READ SLIDE>>Ref:•Vahter M. Health effects of early life exposure to arsenic. Basic Clin Pharmacol Toxicol.2008, 102(2):204-11.Inorganic arsenic is a potent human carcinogen and general toxicant. More than onehundred million people are exposed to elevated concentrations, mainly via drinking water,but also via industrial emissions. Arsenic is metabolized via methylation and reductionreactions, methylarsonic acid and dimethylarsinic acid being the main metabolites excretedin urine. Both inorganic arsenic and its methylated metabolites easily pass the placenta andboth experimental and human studies have shown increased risk of impaired foetal growthand increased foetal loss. Recent studies indicate that prenatal arsenic exposure alsoincreases the risk of adverse effects during early childhood. There is a growing body ofevidence that the intrauterine or early childhood exposure to arsenic also induces changesthat will become apparent much later in life. One epidemiological study indicated thatexposure to arsenic in drinking water during early childhood or in utero was associated withan increased mortality in young adults from both malignant and non-malignant lung disease.Furthermore, a series of experimental animal studies provide strong support for late effectsof arsenic, including various forms of cancer, following intrauterine arsenic exposure. Theinvolved modes of action include epigenetic effects, mainly via DNA hypomethylation,endocrine effects (most classes of steroid hormones), immune suppression, neurotoxicity,and interaction with enzymes critical for foetal development and programming.
  • 38. Children and heavy metals HEALTH EFFECTS OF EARLY LIFE EXPOSURE TO ARSENIC Experimental and human studies have shown: - increased risk of impaired fetal growth - increased fetal loss - increased mortality in young adults from malignant and non- malignant lung disease. Proposed mechanisms: - epigenetic effects, mainly via DNA hypomethylation - endocrine effects (most classes of steroid hormones) - immune suppression - neurotoxicity - interaction with enzymes critical for fetal development and programming Vahter M, 2008 38<<READ SLIDE>>Ref:•Vahter M. Health effects of early life exposure to arsenic. Basic Clin Pharmacol Toxicol.2008, 102(2):204-11.Inorganic arsenic is a potent human carcinogen and general toxicant. More than onehundred million people are exposed to elevated concentrations, mainly via drinking water,but also via industrial emissions. Arsenic is metabolized via methylation and reductionreactions, methylarsonic acid and dimethylarsinic acid being the main metabolites excretedin urine. Both inorganic arsenic and its methylated metabolites easily pass the placenta andboth experimental and human studies have shown increased risk of impaired foetal growthand increased foetal loss. Recent studies indicate that prenatal arsenic exposure alsoincreases the risk of adverse effects during early childhood. There is a growing body ofevidence that the intrauterine or early childhood exposure to arsenic also induces changesthat will become apparent much later in life. One epidemiological study indicated thatexposure to arsenic in drinking water during early childhood or in utero was associated withan increased mortality in young adults from both malignant and non-malignant lung disease.Furthermore, a series of experimental animal studies provide strong support for late effectsof arsenic, including various forms of cancer, following intrauterine arsenic exposure. Theinvolved modes of action include epigenetic effects, mainly via DNA hypomethylation,endocrine effects (most classes of steroid hormones), immune suppression, neurotoxicity,and interaction with enzymes critical for foetal development and programming.
  • 39. Children and heavy metals INCREASED RISK FOR SPONTANEOUS ABORTION, STILLBIRTH INFANT MORTALITY FROM PRENATAL ARSENIC EXPOSURE A dose-effect relationship was found between prenatal arsenic exposure in Bangladesh and infant mortality rate Relative risk of 5 higher/lower quintile Image: Author:Anisur Rahman, Lars-Åke Persson, Barbro Nermell, et al. Publication:Epidemiology. Publisher:Wolters Kluwer Health. Date:Jan 1, 2010. Copyright © 2010, (C) 2010 Lippincott Williams. Reuse According to STM Guidelines. 39A dose-effect relationship was found between prenatal arsenic exposure and infant mortality rate inthis cohort study in Bangladesh.Ref:•Rahman A et al. Arsenic Exposure and Risk of Spontaneous Abortion, Stillbirth, and Infant Mortality.Epidemiology. 2010, 21(6):797-804.Background: Millions of people worldwide are drinking water with elevated arsenic concentrations.Epidemiologic studies, mainly cross-sectional in design, have suggested that arsenic in drinking watermay affect pregnancy outcome and infant health. We assessed the association of arsenic exposurewith adverse pregnancy outcomes and infant mortality in a prospective cohort study of pregnantwomen.Methods: A population-based, prospective cohort study of 2924 pregnant women was carried outduring 2002–2004 in Matlab, Bangladesh. Spontaneous abortion was evaluated in relation to urinaryarsenic concentrations at gestational week 8. Stillbirth and infant mortality were evaluated in relation tothe average of urinary arsenic concentrations measured at gestational weeks 8 and 30.Results: The odds ratio of spontaneous abortion was 1.4 (95% confidence interval [CI] = 0.96–2.2)among women with urine arsenic concentrations in the fifth quintile (249–1253 µg/L; median = 382µg/L), compared with women in the first quintile (<33 µg/L). There was no clear evidence of increasedrates of stillbirth. The rate of infant mortality increased with increasing arsenic exposure: the hazardratio was 5.0 (95% CI = 1.4–18) in the fifth quintile of maternal urinary arsenic concentrations (268–2019 µg/L; median = 390 µg/L), compared with the first quintile (<38 µg/L).Conclusions: We found evidence of increased risk of infant mortality with increasing arsenic exposureduring pregnancy, with less evidence of associations with spontaneous abortion or stillbirth risk.Image: Author:Anisur Rahman, Lars-Åke Persson, Barbro Nermell, et al. Publication:Epidemiology.Publisher:Wolters Kluwer Health. Date:Jan 1, 2010. Copyright © 2010, (C) 2010 Lippincott Williams.Reuse According to STM Guidelines.
  • 40. Children and heavy metals PRENATAL ARSENIC EXPOSURE AND INCREASED RISK FOR PNEUMONIA AND DIARRHEA IN INFANCY Previous studies reported associations between prenatal arsenic exposure and increased risk of infant mortality. Objective: Evaluate association between arsenic exposure in pregnancy and morbidity during infancy. Prospective population-based cohort study in 1,552 live-born infants of women enrolled during 2002-4 in Bangladesh. Arsenic exposure -assessed by the levels of metabolites of inorganic arsenic in maternal urine samples at gestational weeks 8 and 30. Information on symptoms of lower respiratory tract infection (LRTI) and diarrhea in infants - by 7-day recalls at monthly home visits. Rahman A et al, 2011 40 40This study shows an association between arsenic exposure during pregnancy and increased morbidityin infectious diseases during infancy.Ref:•Rahman A et al. Arsenic exposure in pregnancy increases the risk of lower respiratory tract infectionand diarrhea during infancy in Bangladesh. Environmental Health Perspectives. 2011, 119(5):719-24.Background: Previous studies have reported associations between prenatal arsenic exposure andincreased risk of infant mortality. An increase in infectious diseases has been proposed as theunderlying cause of these associations, but there is no epidemiologic research to support thehypothesis.Objective: We evaluated the association between arsenic exposure in pregnancy and morbidity duringinfancy.Methods: This prospective population-based cohort study included 1,552 live-born infants of womenenrolled during 2002–2004 in Matlab, Bangladesh. Arsenic exposure was assessed by theconcentrations of metabolites of inorganic arsenic in maternal urine samples collected at gestationalweeks 8 and 30. Information on symptoms of lower respiratory tract infection (LRTI) and diarrhea ininfants was collected by 7-day recalls at monthly home visits.Results: In total, 115,850 person-days of observation were contributed by the infants during a 12-month follow-up period. The estimated risk of LRTI and severe LRTI increased by 69% [adjustedrelative risk (RR) = 1.69; 95% confidence interval (CI), 1.36–2.09)] and 54% (RR = 1.54; 95% CI,1.21–1.97), respectively, for infants of mothers with urinary arsenic concentrations in the highestquintile (average of arsenic concentrations measured in early and late gestation, 262–977 µg/L)relative to those with exposure in the lowest quintile (< 39 µg/L). The corresponding figure for diarrheawas 20% (RR = 1.20; 95% CI, 1.01–1.43).Conclusions: Arsenic exposure during pregnancy was associated with increased morbidity ininfectious diseases during infancy. Taken together with the previous evidence of adverse effects onhealth, the findings strongly emphasize the need to reduce arsenic exposure via drinking water.
  • 41. Children and heavy metals PRENATAL ARSENIC EXPOSURE AND INCREASED RISK FOR PNEUMONIA AND DIARRHEA IN INFANCY Results: 115,850 person-days of observation were contributed by the infants during 1 year follow-up. Estimated risk of lower respiratory tract infection (LRTI) and severe LRTI increased by 69% and 54%, respectively, for infants of mothers with urinary arsenic in the highest quintile. For diarrhea: corresponding figure of 20% Conclusions: Arsenic exposure during pregnancy was associated with increased morbidity in infectious diseases during infancy. Taken together with the previous evidence of adverse effects on health, the findings strongly emphasize the need to reduce arsenic exposure via drinking water Rahman A et al, 2011 41 41This study shows an association between arsenic exposure during pregnancy and increased morbidityin infectious diseases during infancy.Ref:•Rahman A et al. Arsenic exposure in pregnancy increases the risk of lower respiratory tract infectionand diarrhea during infancy in Bangladesh. Environmental Health Perspectives. 2011, 119(5):719-24.Background: Previous studies have reported associations between prenatal arsenic exposure andincreased risk of infant mortality. An increase in infectious diseases has been proposed as theunderlying cause of these associations, but there is no epidemiologic research to support thehypothesis.Objective: We evaluated the association between arsenic exposure in pregnancy and morbidity duringinfancy.Methods: This prospective population-based cohort study included 1,552 live-born infants of womenenrolled during 2002–2004 in Matlab, Bangladesh. Arsenic exposure was assessed by theconcentrations of metabolites of inorganic arsenic in maternal urine samples collected at gestationalweeks 8 and 30. Information on symptoms of lower respiratory tract infection (LRTI) and diarrhea ininfants was collected by 7-day recalls at monthly home visits.Results: In total, 115,850 person-days of observation were contributed by the infants during a 12-month follow-up period. The estimated risk of LRTI and severe LRTI increased by 69% [adjustedrelative risk (RR) = 1.69; 95% confidence interval (CI), 1.36–2.09)] and 54% (RR = 1.54; 95% CI,1.21–1.97), respectively, for infants of mothers with urinary arsenic concentrations in the highestquintile (average of arsenic concentrations measured in early and late gestation, 262–977 µg/L)relative to those with exposure in the lowest quintile (< 39 µg/L). The corresponding figure for diarrheawas 20% (RR = 1.20; 95% CI, 1.01–1.43).Conclusions: Arsenic exposure during pregnancy was associated with increased morbidity ininfectious diseases during infancy. Taken together with the previous evidence of adverse effects onhealth, the findings strongly emphasize the need to reduce arsenic exposure via drinking water.
  • 42. Children and heavy metals INCREASED CHILDHOOD LIVER CANCER MORTALITY AND ARSENIC IN DRINKING WATER Liawdrinking Increased childhood liverCancer Epidemioland arsenic in J, et al water in northern Chile. cancer mortality Biomarkers Prev. 2008. Arsenic Health Effects Research Program, University of California, Berkeley Data from Chile, following a period of elevated arsenic levels in drinking water (Liaw et al, 2008) For those exposed as young children, liver cancer mortality at ages 0 -19 was especially high: relative risk (RR) for males born during this period was 8.9 (95% CI), 1.7-45.8; P = 0.009 for females, the corresponding RR was 14.1 (95% CI, 1.6-126; P = 0.018); for males and females pooled, the RR was 10.6 (95% CI, 2.9-39.2; CONCLUSION: exposure to arsenic in drinking P < 0.001). water during early childhood may result in an increase in childhood liver cancer mortality. 42This study in Chile shows how exposure to arsenic in drinking water during early childhoodmay result in an increase in childhood liver cancer mortality.Ref:•Liaw J et al. Increased childhood liver cancer mortality and arsenic in drinking water innorthern Chile. Cancer Epidemiol Biomarkers Prev. 2008, 17(8):1982-7.Arsenic in drinking water is an established cause of lung, bladder, and skin cancers in adultsand may also cause adult kidney and liver cancers. Some evidence for these effectsoriginated from region II of Chile, which had a period of elevated arsenic levels in drinkingwater, in particular from 1958 to 1970. This unique exposure scenario provides a rareopportunity to investigate the effects of early-life arsenic exposure on childhood mortality; toour knowledge, this is the first study of childhood cancer mortality and high concentrations ofarsenic in drinking water. In this article, we compare cancer mortality rates under the age of20 in region II during 1950 to 2000 with those of unexposed region V, dividing subjects intothose born before, during, or after the peak exposure period. Mortality from the mostcommon childhood cancers, leukemia and brain cancer, was not increased in the exposedpopulation. However, we found that childhood liver cancer mortality occurred at higher ratesthan expected. For those exposed as young children, liver cancer mortality between ages 0and 19 was especially high: the relative risk (RR) for males born during this period was 8.9[95% confidence interval (95% CI), 1.7-45.8; P = 0.009]; for females, the corresponding RRwas 14.1 (95% CI, 1.6-126; P = 0.018); and for males and females pooled, the RR was 10.6(95% CI, 2.9-39.2; P < 0.001). These findings suggest that exposure to arsenic in drinkingwater during early childhood may result in an increase in childhood liver cancer mortality.Image from Liaw J et al. Increased childhood liver cancer mortality and arsenic in drinkingwater in northern Chile. Cancer Epidemiol Biomarkers Prev. 2008, 17(8):1982-7. Used withcopyright permission. Arsenic Health Effects Research Program, University of California,Berkeley.
  • 43. Children and heavy metals . POTENTIAL INCREASE OF ARSENIC EXCRETION BY FOLIC ACID SUPPLEMENTATION Double blind, placebo-controlled folic acid-supplementation trial in Bangladesh (Gamble et al, 2006) Increase in the proportion of urinary arsenic excreted as dimethylarsinic acid (DMA) in the folic acid group (72% before and 79% after supplementation) (P < 0.0001) greater than that in the placebo group, and reduction in the proportions of total urinary arsenic excreted as monomethylarsonic acid (MMA) (13% and 10%, respectively; P < 0.0001) and as inorganic arsenic (15% and 11%, respectively; P < 0.001). 43This study suggests that folic acid supplementation may reduce the risk of arsenic-related healthoutcomes.Ref:•Gamble MW et al. Folate and Arsenic Metabolism: A double-blind placebo controlled folic acidsupplementation trial in Bangladesh. Am J Clin Nutr. 2006, 84:1093-101.Populations in South and East Asia and many other regions of the world are chronically exposed toarsenic-contaminated drinking water. To various degrees, ingested inorganic arsenic (InAs) ismethylated to monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) via folate-dependentone-carbon metabolism; impaired methylation is associated with adverse health outcomes.Consequently, folate nutritional status may influence arsenic methylation and toxicity.The objective of this study was to test the hypothesis that folic acid supplementation of arsenic-exposed adults would increase arsenic methylation.Design: Two hundred adults in a rural region of Bangladesh, previously found to have low plasmaconcentrations of folate (</=9 nmol/L) were enrolled in a randomized, double-blind, placebo-controlledfolic acid-supplementation trial. Plasma concentrations of folate and homocysteine and urinaryconcentrations of arsenic metabolites were analyzed at baseline and after 12 wk of supplementationwith folic acid at a dose of 400 microg/d or placebo.Results: The increase in the proportion of total urinary arsenic excreted as DMA in the folic acid group(72% before and 79% after supplementation) was significantly (P < 0.0001) greater than that in theplacebo group, as was the reduction in the proportions of total urinary arsenic excreted as MMA (13%and 10%, respectively; P < 0.0001) and as InAs (15% and 11%, respectively; P < 0.001).Conclusions: These data indicate that folic acid supplementation to participants with low plasma folateenhances arsenic methylation. Because persons whose urine contains low proportions of DMA andhigh proportions of MMA and InAs have been reported to be at greater risk of skin and bladdercancers and peripheral vascular disease, these results suggest that folic acid supplementation mayreduce the risk of arsenic-related health outcomes.
  • 44. Children and heavy metals NUTRIENT PROTECTION AGAINST ARSENIC TOXICITY: FOLATE, CYSTEINE SUPPORT METHYLATION IN CHILDREN Nutritional factors are known to influence arsenic metabolism in adults, and poor nutritional status is thought to confer greater susceptibility to arsenic toxicity. Researchers in Bangladesh reported that deficits in the B vitamin folate and the amino acid cysteine may adversely influence arsenic metabolism in children (Hall MN, 2009). Compared with adults, children may metabolize arsenic more efficiently and excrete it more readily, regardless of folate status. Study’s findings indicate that improved nutritional status could constitute a key strategy for reducing the risk of arsenic-related disease in Bangladeshi children (Freeman K. 2009) 44•Nutritional factors are known to influence arsenic metabolism in adults, and poor nutritionalstatus—as reflected in part by a lack of various B vitamins and antioxidants—is thought toconfer greater susceptibility to arsenic toxicity.•Researchers working in Bangladesh have reported that deficits in the B vitamin folate andthe amino acid cysteine may adversely influence arsenic metabolism in children (Hall MN,2009).•Compared with adults, children may metabolize arsenic more efficiently and excrete it morereadily, regardless of folate status.•Overall, this study’s findings indicate that improved nutritional status could constitute a keystrategy for reducing the risk of arsenic-related disease in Bangladeshi children (Freeman K,2009)Refs:•Freeman K. Nutrient Protection against Arsenic Toxicity: Folate, Cysteine SupportMethylation in Children. Environmental Health Perspectives. 2009, 117:A211.•Hall MN et al. Folate, Cobalamin, Cysteine, Homocysteine, and Arsenic Metabolism amongChildren in Bangladesh. Environmental Health Perspectives. 2009, 117:825-831.
  • 45. Children and heavy metals SELECTED HEAVY METALS CADMIUM 45General description of cadmium: A soft, bluish-white metallic element occurring primarily inZinc, Copper and Lead ores, that is easily cut with a knife and is used in low-friction, fatigue-resistant alloys, solders, dental amalgams, Nickel-cadmium storage batteries, nuclearreactor shields, and in rustproof electroplating. Cadmium is soluble in acids but not in alkalis.It is similar in many respects to zinc. The Atomic number is 48.
  • 46. Children and heavy metals PROPERTIES AND SOURCES OF CADMIUM A silvery, crystalline metal Sources: USGS - Smelting and soldering - Batteries - Electroplating USEPA - Plasticizers - Pigments - Alloys - Nuclear industry - Cigarette smoke WHO 46Cadmium exerts toxic effects on the kidney, the skeletal and the respiratory systems, and isclassified as a human carcinogen. It is generally present in the environment at low levels.However, human activity has greatly increased those levels. Cadmium can travel longdistances from the source of emission by atmospheric transfer. It is readily accumulated inmany organisms, notably molluscs and crustaceans. Lower concentrations are found invegetables, cereals and starchy roots. Human exposure occurs mainly from consumption ofcontaminated food, active and passive inhalation of tobacco smoke, and inhalation byworkers in the non-ferrous metal industry.Ref:•Waalkes M, Wahba ZZ, Rodriguez E. Cadmium. In: Sullivan JB Jr. Krieger GR. ClinicalEnvironmental Health and Toxic Exposures. 2nd Edition. Lippincott Williams & Wilkins. 2001.•WHO. Cadmium. 10 Chemicals of major public health concern. Available atwww.who.int/ipcs/features/cadmium.pdf - accessed 22 September 2011.Image on top from US Geological Survey (USGS). Available athttp://geomaps.wr.usgs.gov/parks/rxmin/rock.html - accessed 22 September 2011Image in the middle from US Environmental Protection Agency (USEPA). Available atwww.epa.gov/osw/conserve/materials/battery.html - accessed 22 September 2011Image in the bottom: young girl smoking, Lao Peoples Democratic Republics, 2008. JimHolmes, WHO
  • 47. Children and heavy metals CADMIUM - EXPOSURE SOURCES AND ABSORPTION Foods: grains, cereals, leafy vegetables - only 5% is absorbed Itai Itai disease (cadmium contamination + diet low in calcium & vitamin D) Inhalation: fumes, dust, cigarettes: > 90% is absorbed WHO WHO 47Cadmium can be released to the environment in a number of ways, including:•natural activities, such as volcanic activity (both on land and in the deep sea), weatheringand erosion, and river transport;•human activities, such as tobacco smoking, mining, smelting and refining of non-ferrousmetals,6 fossil fuel combustion, incineration of municipal waste (especially cadmium-containing batteries and plastics), manufacture of phosphate fertilizers, and recycling ofcadmium-plated steel scrap and electric and electronic waste7;•remobilization of historic sources, such as the contamination of watercourses by drainagewater from metal mines.Cadmium releases can be carried to and deposited on areas remote from the sources ofemission by means of long-range atmospheric transport.Note: Itai Itai disease is a form of renal osteodystrophy—osteomalacia with marked bonepain and painful fractures. It means "ouch ouch" in Japanese and was described inJapanese women due to cadmium accumulation in bone, caused by industrial pollutants.Refs:•Waalkes M, Wahba ZZ, Rodriguez E. Cadmium. In: Sullivan JB Jr. Krieger GR. ClinicalEnvironmental Health and Toxic Exposures. 2nd Edition. Lippincott Williams & Wilkins. 2001.•WHO. Cadmium. 10 Chemicals of major public health concern. Available atwww.who.int/ipcs/features/cadmium.pdf - accessed 22 September 2011.
  • 48. Children and heavy metals EXPOSURE SOURCE FOR CADMIUM – TOBACCO Tobacco smoke: a one pack a day smoker absorbs roughly 5 -10 times the amount absorbed from the average daily diet Cadmium in breast milk of smoking women Cigarette smoking can cause significant increases in the concentrations of cadmium in the kidney, the main target organ for cadmium toxicity. 48The tobacco plant naturally accumulates relatively high concentrations of cadmium in itsleaves. Thus, smoking tobacco is an important source of exposure, and the daily intake mayexceed that from food in the case of heavy smokers. Cigarette smoking can cause significantincreases in the concentrations of cadmium in the kidney, the main target organ for cadmiumtoxicity.<<READ SLIDE>>Refs:•Radisch B, Luck w, Nau H. Cadmium Concentrations in Milk and Blood of SmokingMothers. Toxicology Letters. 1987, 36:147-152.•WHO. Cadmium. 10 Chemicals of major public health concern. Available atwww.who.int/ipcs/features/cadmium.pdf - accessed 22 September 2011.
  • 49. Children and heavy metals EXPOSURE SOURCE FOR CADMIUM – TOBACCO Metal content in the tobacco comes from the soil, concentrated by tobacco plants Cadmium is used in cigarette paper to make the paper burn slower Cigarette tobacco contains about 0.5 - 2.0 µg of cadmium and about 10% of the cadmium content is inhaled when cigarette is smoked (WHO 1992) Non-smoker may passively inhale significant amount of cadmium along with inhaled tobacco smoke 49•The metal content in the tobacco comes from the soil, which is being concentrated bytobacco plants.•Cadmium is used in cigarette paper to make the paper burn slower. These metals are eitherreleased into the air by tobacco smoke or are retained in the cigarette ash.•A cigarettes tobacco contains about 0.5 - 2.0 µg of cadmium and about 10% of thecadmium content is inhaled when the cigarette is smoked (WHO 1992).•The non-smoker may passively inhales significant amount of cadmium along with inhaledtobacco smoke.Ref:•WHO. Environmental Health Criteria 134 - Cadmium International Programme on ChemicalSafety (IPCS) Monograph. WHO. 1992.
  • 50. Children and heavy metals CADMIUM - METABOLISM AND EXCRETION It has no known beneficial function in the human body It is transported in the blood bound to metallothionein Greatest concentrations in kidneys & liver Urinary excretion is slow Biologic half-life may last 25-30 years 50<<READ SLIDE>>Ref:•Waalkes M, Wahba ZZ, Rodriguez E. Cadmium. In: Sullivan JB Jr. Krieger GR. ClinicalEnvironmental Health and Toxic Exposures. 2nd Edition. Lippincott Williams & Wilkins. 2001.
  • 51. Children and heavy metals MECHANISM OF CADMIUM TOXICITY Interacts with essential nutrients Competes with gastrointestinal absorption of zinc, inhibits zinc enzymes Decreases copper in liver & plasma Binds to ferritin, decreases hemoglobin – anemia Deposits in bones Does not generate free oxygen radicals Interaction of cadmium with essential nutrients by which it causes its toxic effects. Flora SJ et al. Heavy metal induced oxidative stress & its possible reversal by chelation therapy. Indian J Med Res. 2008. 128(4):501-23. 51This slide presents the main mechanisms of cadmium toxicity. Specific acute and chronictoxicity are addressed in the upcoming slides.<<READ SLIDE>>Ref:•Flora SJ, Mittal M, Mehta A. Heavy metal induced oxidative stress & its possible reversal bychelation therapy. Indian J Med Res. 2008. 128(4):501-23.Image from Flora SJ, Mittal M, Mehta A. Heavy metal induced oxidative stress & its possiblereversal by chelation therapy. Indian J Med Res. 2008. 128(4):501-23. Used with copyrightpermission. Copyright expires October 2014.
  • 52. Children and heavy metals CADMIUM - ACUTE TOXICITY Ingestion: - Gastrointestinal symptoms: nausea, vomiting, abdominal pain, diarrhea, salivation, tenesmus, hemorrhagic gastroenteritis - Hepatic necrosis - Renal necrosis - Cardiomyopathy Inhalation (fumes): - Respiratory: nasopharyngeal irritation, chest pain, dyspnea - Cadmium fume pneumonitis, potentially fatal! - May result in pulmonary fibrosis - Other: headache, dizziness, chills, weakness 52<<READ SLIDE>>Note: Knowledge about acute toxicity comes mostly from the industrial exposures of adults.Ref:•Waalkes M, Wahba ZZ, Rodriguez E. Cadmium. In: Sullivan JB Jr. Krieger GR. ClinicalEnvironmental Health and Toxic Exposures. 2nd Edition. Lippincott Williams & Wilkins. 2001.
  • 53. Children and heavy metals CADMIUM - CHRONIC TOXICITY Respiratory: - Chronic obstructive lung disease (COPD) - Lung fibrosis (restrictive) - Lung cancer Renal: - Proximal tubular necrosis - Proteinuria, secretion of beta 2 microglobulin Skeletal: - Osteomalacia & osteoporosis - Bone pain (Itai-Itai) Cardiovascular: hypertension Cancer: lungs, kidney, prostate and stomach Other: anosmia 53<<READ SLIDE>>Note: Itai Itai disease is a form of renal osteodystrophy—osteomalacia with marked bonepain and painful fractures. It means "ouch ouch" in Japanese and was described inJapanese women due to cadmium accumulation in bone, caused by industrial pollutantsRef:•Waalkes M, Wahba ZZ, Rodriguez E. Cadmium. In: Sullivan JB Jr. Krieger GR. ClinicalEnvironmental Health and Toxic Exposures. 2nd Edition. Lippincott Williams & Wilkins. 2001.
  • 54. Children and heavy metals EFFECTS OF GESTATIONAL CADMIUM EXPOSURE ON PREGNANCY OUTCOME AND DEVELOPMENT IN THE OFFSPRING AT AGE 4 ½ YEARS Objective: To evaluate the potential effect of maternal cadmium exposure on pregnancy outcome and development in the offspring at age 4 ½ years. Methods: Between November 2002 and December 2003, 109 normal pregnant women were enrolled in in Central China. - Placental, whole blood, and cord blood levels of cadmium were determined - 106 children at 4 ½ years of age were followed up - Questionnaire surveys, anthropometric measurements and IQ development was evaluated by Wechsler Preschool and Primary Scale of Intelligence (WPPSI-R). Tian LL et al. 2009 54Ref:•Tian LL et al. Effects of gestational cadmium exposure on pregnancy outcome and development inthe offspring at age 4.5 years. Biol Trace Elem Res. 2009, 132(1-3):51-9.The objective of the present study was to evaluate the potential effect of maternal cadmium exposureon pregnancy outcome and development in the offspring at age 4.5 years. Between November 2002and December 2003, 109 normal pregnant women were enrolled in our cohort from Da-Ye Country,Hubei Province in Central China. The placental, whole blood, and cord blood levels of cadmium weredetermined by inductively coupled plasma mass spectrometer (ICP-MS). The 106 children at 4.5 yearsof age given birth by the aforementioned women were followed up and the following rate was 97.25%.Detailed questionnaire surveys, anthropometric measurements were performed, and IQ developmentwas evaluated by Wechsler Preschool and Primary Scale of Intelligence Revised Edition (WPPSI-R).Multiple linear regression analysis indicated that cord blood cadmium level was significantly negativelycorrelated with fetus development. Low birth weight (less than 2,500 g) occurred significantly morefrequently in infants with higher cord blood cadmium than in those exposed to lower levels of cordblood cadmium. Significantly negative correlation was found between cord blood cadmium exposureand WPPSI-R IQ full score after controlling for confounding variables. It was concluded that cord bloodcadmium concentration was a factor that influenced fetus growth and later IQ development.
  • 55. Children and heavy metals EFFECTS OF GESTATIONAL CADMIUM EXPOSURE ON PREGNANCY OUTCOME AND DEVELOPMENT IN THE OFFSPRING AT AGE 4 ½ YEARS Results: - Cord blood cadmium - significantly negatively correlated with fetus development - Low birth weight (<2,500 g) significantly more frequent in infants with higher cord blood cadmium than in those exposed to lower levels of cord blood cadmium. - Significantly negative correlation was found between cord blood cadmium exposure and Wechsler Preschool and Primary Scale of Intelligence Revised Edition (WPPSI-R) IQ full score Conclusion: Cord blood cadmium influenced fetal growth and later IQ development Tian LL et al. 2009 55This study shows a link between cord blood cadmium concentration and fetal growth and later IQdevelopment.Ref:•Tian LL et al. Effects of gestational cadmium exposure on pregnancy outcome and development inthe offspring at age 4.5 years. Biol Trace Elem Res. 2009, 132(1-3):51-9.The objective of the present study was to evaluate the potential effect of maternal cadmium exposureon pregnancy outcome and development in the offspring at age 4.5 years. Between November 2002and December 2003, 109 normal pregnant women were enrolled in our cohort from Da-Ye Country,Hubei Province in Central China. The placental, whole blood, and cord blood levels of cadmium weredetermined by inductively coupled plasma mass spectrometer (ICP-MS). The 106 children at 4.5 yearsof age given birth by the aforementioned women were followed up and the following rate was 97.25%.Detailed questionnaire surveys, anthropometric measurements were performed, and IQ developmentwas evaluated by Wechsler Preschool and Primary Scale of Intelligence Revised Edition (WPPSI-R).Multiple linear regression analysis indicated that cord blood cadmium level was significantly negativelycorrelated with fetus development. Low birth weight (less than 2,500 g) occurred significantly morefrequently in infants with higher cord blood cadmium than in those exposed to lower levels of cordblood cadmium. Significantly negative correlation was found between cord blood cadmium exposureand WPPSI-R IQ full score after controlling for confounding variables. It was concluded that cord bloodcadmium concentration was a factor that influenced fetus growth and later IQ development.
  • 56. Children and heavy metals EFFECT OF ENVIRONMENTAL EXPOSURE TO CADMIUM ON PREGNANCY OUTCOME AND FETAL GROWTH: A STUDY ON HEALTHY PREGNANT WOMEN IN CHINA Objective To evaluate the potential effect of gestational cadmium exposure on pregnancy outcome and fetal growth. Methods: Normal pregnant women from a cadmium-polluted area (2002-2003) - Cadmium levels measured in whole blood of pregnant women, cord blood, and placenta. - Incidence rate of preterm labor (< or = 37 weeks) and neonatal asphyxia, neonatal birth height, and birth weight were compared between lower and higher cadmium exposure level groups. - Whole blood cadmium of 44 mothers ranged from 0.8 to 25.20 ug/L. Cadmium in maternal blood was significantly higher than that in cord blood (t = 11.44, P < 0.01). Placenta cadmium ranged from 0.084 to 3.97 ug/g dry weight. Zhang YL et al, 2004 56This study shows a link between gestational environmental exposure to cadmium and significantlylower neonatal birth height.Ref:•Zhang YL et al. Effect of environmental exposure to cadmium on pregnancy outcome and fetalgrowth: a study on healthy pregnant women in China. J Environ Sci Health A Tox Hazard SubstEnviron Eng. 2004. 39(9):2507-15.The objective of the present study was to evaluate the potential effect of environmental exposure tocadmium on pregnancy outcome and fetal growth. Normal pregnant women were selected from Da-yecity of Hubei province, a cadmium-polluted area, from November 2002 through January 2003. Wholeblood of pregnant women, cord blood, and placenta were collected and cadmium levels weredetermined by inductively coupled plasma emission mass spectroscopy. Incidence rate of pretermlabor (gestational age < or = 37 weeks) and neonatal asphyxia, neonatal birth height, and birth weightwere compared between lower and higher cadmium exposure level groups. Whole blood cadmium of44 mothers ranged from 0.80 to 25.20 microg/L. Cadmium concentration in maternal blood wassignificantly higher than that in cord blood (t = 11.44, P < 0.01). Placenta cadmium ranged from 0.084to 3.97 microg/g dry weight. After adjustment for maternal age, history of gestation, abortion andlactation, Logistic regression analysis showed that there was no significant association betweencadmium exposure levels and pregnancy outcome (premature labor or neonatal asphyxia). Multiplelinear regression analysis showed that, cord blood cadmium level, but not maternal blood cadmiumand placenta cadmium, was significantly negatively associated with neonatal birth height (t= -2.33, P <0.05). Compared with lower cord blood cadmium level (< or = 0.40 microg/L), higher level of cordblood cadmium (>0.40 microg/L) was associated with 2.24cm decrease in neonatal birth height. Therewas no significant association between cadmium exposure and birth weight. It was concluded thatenvironmental exposure to cadmium significantly lower neonatal birth height.
  • 57. Children and heavy metals EFFECT OF ENVIRONMENTAL EXPOSURE TO CADMIUM ON PREGNANCY OUTCOME AND FETAL GROWTH: A STUDY ON HEALTHY PREGNANT WOMEN IN CHINA Results: - No significant association between cadmium exposure levels and pregnancy outcome (premature labor or neonatal asphyxia) - Cord blood cadmium, but not maternal blood cadmium and placenta cadmium, was significantly negatively associated with neonatal birth height (t= -2.33, P < 0.05) - Compared with lower cord blood cadmium (< or = 0.40 ug/L), higher level of cord blood cadmium (>0.40 ug/L) was associated with 2.24 cm decrease in neonatal birth height. - No significant association between cadmium exposure and birth weight. Conclusion: Environmental exposure to cadmium significantly lower neonatal birth height. Zhang YL et al, 2004 57This study shows a link between environmental exposure to cadmium and significantly lower neonatalbirth height.Ref:•Zhang YL et al. Effect of environmental exposure to cadmium on pregnancy outcome and fetalgrowth: a study on healthy pregnant women in China. J Environ Sci Health A Tox Hazard SubstEnviron Eng. 2004. 39(9):2507-15.The objective of the present study was to evaluate the potential effect of environmental exposure tocadmium on pregnancy outcome and fetal growth. Normal pregnant women were selected from Da-yecity of Hubei province, a cadmium-polluted area, from November 2002 through January 2003. Wholeblood of pregnant women, cord blood, and placenta were collected and cadmium levels weredetermined by inductively coupled plasma emission mass spectroscopy. Incidence rate of pretermlabor (gestational age < or = 37 weeks) and neonatal asphyxia, neonatal birth height, and birth weightwere compared between lower and higher cadmium exposure level groups. Whole blood cadmium of44 mothers ranged from 0.80 to 25.20 microg/L. Cadmium concentration in maternal blood wassignificantly higher than that in cord blood (t = 11.44, P < 0.01). Placenta cadmium ranged from 0.084to 3.97 microg/g dry weight. After adjustment for maternal age, history of gestation, abortion andlactation, Logistic regression analysis showed that there was no significant association betweencadmium exposure levels and pregnancy outcome (premature labor or neonatal asphyxia). Multiplelinear regression analysis showed that, cord blood cadmium level, but not maternal blood cadmiumand placenta cadmium, was significantly negatively associated with neonatal birth height (t= -2.33, P <0.05). Compared with lower cord blood cadmium level (< or = 0.40 microg/L), higher level of cordblood cadmium (>0.40 microg/L) was associated with 2.24cm decrease in neonatal birth height. Therewas no significant association between cadmium exposure and birth weight. It was concluded thatenvironmental exposure to cadmium significantly lower neonatal birth height.
  • 58. Children and heavy metals CADMIUM - TREATMENT & MANAGEMENT Acute exposure Diagnose by symptoms Laboratory: Cadmium, levels in blood & urine renal dysfunction: albumin, creatinine, β2-microglobulin, retinol binding proteins Supportive treatment - Following ingestion, gastric decontamination - Immediately after acute exposure, Calcium Disodium Versante (CaNa2-EDTA) may be effective Chronic – Prevent further exposure Chelation is ineffective due to the high affinity of cadmium to metallothionein Experimental therapy with a combining deferasirox and deferiprone was effective in rats (Jamilaldin Fatemi et al, 2011) 58This slide presents treatment and management options for dealing with acute and chronicexposure to cadmium. For chronic exposures, the best strategy is to prevent furtherexposure.Refs:•Jamilaldin Fatemi S et al. Chelation of cadmium by combining deferasirox and deferipronein rats. Toxicol Ind Health. 2011. 27(4):371-7.•Waalkes M, Wahba ZZ, Rodriguez E. Cadmium. In: Sullivan JB Jr. Krieger GR. ClinicalEnvironmental Health and Toxic Exposures. 2nd Edition. Lippincott Williams & Wilkins. 2001.
  • 59. Children and heavy metals SELECTED HEAVY METALS COPPER 59Copper – general description: Copper is a reddish-brown, ductile and malleable metal. Itbelongs to group IB of the Periodic Table. In compounds found in the environment it usuallyhas a valence of 2 but can exist in the metallic, +1 and +3 valence states. Copper is foundnaturally in a wide variety of mineral salts and organic compounds, and in the metallic form.The metal is sparingly soluble in water, salt or mildly acidic solutions, but can be dissolved innitric and sulfuric acids as well as basic solutions of ammonium hydroxide or carbonate.Copper possesses high electrical and thermal conductivity and resists corrosion.Ref:•IPCS. Copper. Environmental Health Criteria 200. WHO, 1998.
  • 60. Children and heavy metals COPPER – PROPERTIES, ROLES AND TOXICITY Metallic copper – resistant to corrosion Copper compounds (oxide, sulfates, and others) may be toxic PHYSIOLOGY: - Normal copper homeostasis is essential for human growth and development, a cofactor in enzymes DEFICIENCY: - cardiac hypertrophy - poor neuronal myelination - blood vessel abnormalities - impaired immune response. TOXICITY: (copper sulfate was a popular murder weapon and abortifacient) - Gastrointestinal, respiratory, renal, hematological symptoms 60Refs:•Fisher DC. Copper. In: Sullivan JB Jr. Krieger GR. Clinical Environmental Health and ToxicExposures. 2nd Edition, Lippincott Williams & Wilkins, 2001.•Gupta A, Lutsenko S. Human copper transporters: mechanism, role in human diseases andtherapeutic potential. Future Med Chem. 2009, 1(6):1125-42.
  • 61. Children and heavy metals COPPER – SOURCES AND ABSORPTION Sources: Mines Contaminated drinking water Pesticides Metallurgic industry Absorption: Ingestion: in diet – 1.2 – 5 mg / day (50% absorbed) Inhalation: dust, fumes in industrial setting (in adults) 61Natural sources of copper exposure include windblown dust, volcanoes, decayingvegetation, forest fires and sea spray. Anthropogenic emissions include smelters, ironfoundries, power stations and combustion sources such as municipal incinerators. The majorrelease of copper to land is from tailings and overburdens from copper mines and sewagesludge. Agricultural use of copper products accounts for 2% of copper released to soil.Copper ores are mined, smelted and refined to produce many industrial and commercialproducts. Copper is widely used in cooking utensils and water distribution systems, as wellas fertilizers, bactericides, fungicides, algicides and antifouling paints. It is also used inanimal feed additives and growth promoters, as well as for disease control in livestock andpoultry. Copper is used in industry as an activator in froth flotation of sulfide ores, productionof wood preservatives, electroplating, azo-dye manufacture, as a mordant for textile dyes, inpetroleum refining and the manufacture of copper compounds.Ref:•Fisher DC. Copper. In: Sullivan JB Jr. Krieger GR. Clinical Environmental Health and ToxicExposures. 2nd Edition, Lippincott Williams & Wilkins, 2001.•IPCS. Copper. Environmental Health Criteria 200. WHO, 1998.
  • 62. Children and heavy metals COPPER – MOSTLY ACUTE TOXICITY Usually mild overdose, due to its emetic effect Intentional- suicidal setting, may be severe and fatal Symptoms: - Gastrointestinal: metallic taste, nausea, vomiting, gastrointestinal bleeding - Renal: hematuria, oliguria, elevated urea and creatinine, acute tubular necrosis - Hematological: hemolytic anemia - Respiratory: metal fume fever – industrial setting – nasal congestion, fever, chills, malaise, shortness of breath, resolve over weekends and recur Chronic – rare (except Wilson’s disease, genetic-metabolic) 62Ref:•Fisher DC. Copper. In: Sullivan JB Jr. Krieger GR. Clinical Environmental Health and ToxicExposures. 2nd Edition, Lippincott Williams & Wilkins, 2001.
  • 63. Children and heavy metals SELECTED HEAVY METALS THALLIUM 63
  • 64. Children and heavy metals THALLIUM – PROPERTIES and SOURCES Soft, white blue Colorless, tasteless, odorless When exposed to air, oxidizes and forms thallium oxide Sources: small quantities, industrial sources: - electronics - optical glasses - semiconductors - scintillation counters - mercury lamps - medical device – scintigraphy for the heart, liver and other tissues - jewelry - pigments - rodenticide 64Ref:•Sullivan JB, Jr. Thallium. In: Sullivan JB Jr. Krieger GR. Clinical Environmental Health andToxic Exposures. 2nd Edition, Lippincott Williams & Wilkins, 2001
  • 65. Children and heavy metals THALLIUM - ABSORPTION, DISTRIBUTION AND EXCRETION Bioavailability, almost 100% by: ingestion, inhalation and dermal exposure Distribution: intracellular, mainly renal, also heart and liver Excretion: weeks (elimination t½ - 10-30 days) 65Ref:•Sullivan JB, Jr. Thallium. In: Sullivan JB Jr. Krieger GR. Clinical Environmental Health andToxic Exposures. 2nd Edition, Lippincott Williams & Wilkins, 2001
  • 66. Children and heavy metals THALLIUM – ACUTE TOXICITY Thallium is highly toxic (lethal oral dose – 6-40 mg/kg) Suicide / homicide Triad: - Gastrointestinal: anorexia, vomiting, gastrointestinal bleed, abdominal pain - Polyneuropathy – paresthesia, distal weakness - Alopecia (after 2 weeks) Later symptoms: psychosis, seizures, fatigue, emotional changes, renal failure, skin erythema, autonomic dysfunction, coma, delirium, hallucinations, lens opacities, cardiotoxicity with arrhythmias, potentially fatal 66<<READ SLIDE>>Thallium poisoning can be mistaken for botulism.Please note the information on this slide comes mostly from adult exposure data.Ref:•Sullivan JB, Jr. Thallium. In: Sullivan JB Jr. Krieger GR. Clinical Environmental Health andToxic Exposures. 2nd Edition, Lippincott Williams & Wilkins, 2001
  • 67. Children and heavy metals TREATMENT OF THALLIUM TOXICITY Supportive No effective chelating agent Potassium (increases urinary thallium excretion) Potassium ferric-cyanoferrate ll (Prussian blue) orally Activated charcoal, cathartics 67Since there is no specific treatment of thallium toxicity, the mainstay treatment is:•reducing absorption•increasing its elimination•and supportive treatment.
  • 68. Children and heavy metals CONTROVERSIES ABOUT ISSUES ASSOCIATED WITH EXPOSURE TO HEAVY METALS 68The question of the possible association of heavy metals and child health has frequentlyarisen during the last 50 years due to an increased incidence of autism, the presence ofheavy metals as vaccine preservatives and other concerns. The following slides addresssome of these questions based on evidence and existing data.
  • 69. Children and heavy metals CONTROVERSY: LINKAGE BETWEEN HEAVY METALS AND AUTISM? Rationale: neuro-toxic effect of heavy metals: - Arsenic - Lead - Mercury Ecological linkage: rising incidence of autism in the 1990’s Increased exposure to mercury? Mercury is a neurodevelopmental poison; it can cause problems in neuronal cell migration and division, and can ultimately cause cell degeneration and death 69The link between heavy metals and autism is presently an area of research. Final conclusions on thisare premature at this moment.
  • 70. Children and heavy metals NO CAUSAL RELATIONSHIP BETWEEN CHILDHOOD VACCINATION WITH THIOMERSAL-CONTAINING VACCINES THIOMERSAL- AND DEVELOPMENT OF AUTISM-SPECTRUM DISORDERS AUTISM- Mercuric compounds are neurotoxic at high doses Thiomersal (thimerosal), a preservative used in vaccines, contains ethyl- mercury Studies of childhood vaccination with thiomersal-containing vaccine do not support link to autism Population-based cohort study of 467,450 children born in Denmark (1990 -1996) comparing children vaccinated with a thiomersal-containing vaccine with children vaccinated with a thiomersal-free vaccine. 70Refs:•Hyiid A et al. Association between thimerosal-containing vaccine and autism. Journal of the American Medical Association, 1:290(13):1763-6.Mercuric compounds are nephrotoxic and neurotoxic at high doses. Thimerosal, a preservative used widely in vaccine formulations, containsethylmercury. Thus it has been suggested that childhood vaccination with thimerosal-containing vaccine could be causally related to neurodevelopmentaldisorders such as autism.OBJECTIVE: To determine whether vaccination with a thimerosal-containing vaccine is associated with development of autism.DESIGN, SETTING, AND PARTICIPANTS: Population-based cohort study of all children born in Denmark from January 1, 1990, until December 31,1996 (N = 467 450) comparing children vaccinated with a thimerosal-containing vaccine with children vaccinated with a thimerosal-free formulation of thesame vaccine.MAIN OUTCOME MEASURES: Rate ratio (RR) for autism and other autistic-spectrum disorders, including trend with dose of ethylmercury.RESULTS: During 2 986 654 person-years, we identified 440 autism cases and 787 cases of other autistic-spectrum disorders. The risk of autism andother autistic-spectrum disorders did not differ significantly between children vaccinated with thimerosal-containing vaccine and childrenvaccinated with thimerosal-free vaccine (RR, 0.85 [95% confidence interval [CI], 0.60-1.20] for autism; RR, 1.12 [95% CI, 0.88-1.43] for other autistic-spectrum disorders). Furthermore, we found no evidence of a dose-response association (increase in RR per 25 microg of ethylmercury, 0.98 [95% CI,0.90-1.06] for autism and 1.03 [95% CI, 0.98-1.09] for other autistic-spectrum disorders).CONCLUSION: The results do not support a causal relationship between childhood vaccination with thimerosal-containing vaccines and development ofautistic-spectrum disorders.•Madsen KM et al. Thimerosal and the occurrence of autism: negative ecological evidence from Danish population-based data. Pediatrics. 2003,112(3):604-6.It has been suggested that thimerosal, a mercury-containing preservative in vaccines, is a risk factor for the development of autism. We examinedwhether discontinuing the use of thimerosal-containing vaccines in Denmark led to a decrease in the incidence of autism.DESIGN: Analysis of data from the Danish Psychiatric Central Research Register recording all psychiatric admissions since 1971, and all outpatientcontacts in psychiatric departments in Denmark since 1995.PATIENTS: All children between 2 and 10 years old who were diagnosed with autism during the period from 1971-2000.OUTCOME MEASURES: Annual and age-specific incidence for first day of first recorded admission with a diagnosis of autism in children between 2 and10 years old.RESULTS: A total of 956 children with a male-to-female ratio of 3.5:1 had been diagnosed with autism during the period from 1971-2000. There was notrend toward an increase in the incidence of autism during that period when thimerosal was used in Denmark, up through 1990. From 1991 until 2000 theincidence increased and continued to rise after the removal of thimerosal from vaccines, including increases among children born after thediscontinuation of thimerosal.CONCLUSIONS: The discontinuation of thimerosal-containing vaccines in Denmark in 1992 was followed by an increase in the incidence of autism. Ourecological data do not support a correlation between thimerosal-containing vaccines and the incidence of autism.•Stehr-Green P et al. Autism and thimerosal-containing vaccines: lack of consistent evidence for an association. Am J Prev Med. 2003, 25: 101-6In 1999, concerns were raised that vaccines containing the preservative Thimerosal might increase the risk of autism and/or other neurodevelopmentaldisorders.METHODS: Between the mid-1980s through the late-1990s, we compared the prevalence/incidence of autism in California, Sweden, and Denmark withaverage exposures to Thimerosal-containing vaccines. Graphic ecologic analyses were used to examine population-based data from the United States(national immunization coverage surveys and counts of children diagnosed with autism-like disorders seeking special education services in California);Sweden (national inpatient data on autism cases, national vaccination coverage levels, and information on use of all vaccines and vaccine-specificamounts of Thimerosal); and Denmark (national registry of inpatient/outpatient-diagnosed autism cases, national vaccination coverage levels, andinformation on use of all vaccines and vaccine-specific amounts of Thimerosal).RESULTS: In all three countries, the incidence and prevalence of autism-like disorders began to rise in the 1985-1989 period, and the rate of increaseaccelerated in the early 1990s. However, in contrast to the situation in the United States, where the average Thimerosal dose from vaccines increasedthroughout the 1990s, Thimerosal exposures from vaccines in both Sweden and Denmark-already low throughout the 1970s and 1980s-began todecrease in the late 1980s and were eliminated in the early 1990s.CONCLUSIONS: The body of existing data, including the ecologic data presented herein, is not consistent with the hypothesis that increased exposure toThimerosal-containing vaccines is responsible for the apparent increase in the rates of autism in young children being observed worldwide.
  • 71. Children and heavy metals NO CAUSAL RELATIONSHIP BETWEEN CHILDHOOD VACCINATION WITH THIOMERSAL-CONTAINING VACCINES THIOMERSAL- AND DEVELOPMENT OF AUTISM-SPECTRUM DISORDERS AUTISM- Risk of autism and other autistic-spectrum disorders did not differ significantly between children vaccinated with thiomersal-containing vaccine and children vaccinated with thiomersal-free vaccine (relative risk 0.85 for autism; relative risk 1.12 for other autism-spectrum disorders Ecological studies of the prevalence/incidence of autism in California, Sweden yielded similar results Studies do not show a causal relationship between childhood vaccination with thiomersal-containing vaccines and autism- spectrum disorders 71Refs:•Hyiid A et al. Association between thimerosal-containing vaccine and autism. Journal of the American Medical Association, 1:290(13):1763-6.Mercuric compounds are nephrotoxic and neurotoxic at high doses. Thimerosal, a preservative used widely in vaccine formulations, containsethylmercury. Thus it has been suggested that childhood vaccination with thimerosal-containing vaccine could be causally related to neurodevelopmentaldisorders such as autism.OBJECTIVE: To determine whether vaccination with a thimerosal-containing vaccine is associated with development of autism.DESIGN, SETTING, AND PARTICIPANTS: Population-based cohort study of all children born in Denmark from January 1, 1990, until December 31,1996 (N = 467 450) comparing children vaccinated with a thimerosal-containing vaccine with children vaccinated with a thimerosal-free formulation of thesame vaccine.MAIN OUTCOME MEASURES: Rate ratio (RR) for autism and other autistic-spectrum disorders, including trend with dose of ethylmercury.RESULTS: During 2 986 654 person-years, we identified 440 autism cases and 787 cases of other autistic-spectrum disorders. The risk of autism andother autistic-spectrum disorders did not differ significantly between children vaccinated with thimerosal-containing vaccine and childrenvaccinated with thimerosal-free vaccine (RR, 0.85 [95% confidence interval [CI], 0.60-1.20] for autism; RR, 1.12 [95% CI, 0.88-1.43] for other autistic-spectrum disorders). Furthermore, we found no evidence of a dose-response association (increase in RR per 25 microg of ethylmercury, 0.98 [95% CI,0.90-1.06] for autism and 1.03 [95% CI, 0.98-1.09] for other autistic-spectrum disorders).CONCLUSION: The results do not support a causal relationship between childhood vaccination with thimerosal-containing vaccines and development ofautistic-spectrum disorders.•Madsen KM et al. Thimerosal and the occurrence of autism: negative ecological evidence from Danish population-based data. Pediatrics. 2003,112(3):604-6.It has been suggested that thimerosal, a mercury-containing preservative in vaccines, is a risk factor for the development of autism. We examinedwhether discontinuing the use of thimerosal-containing vaccines in Denmark led to a decrease in the incidence of autism.DESIGN: Analysis of data from the Danish Psychiatric Central Research Register recording all psychiatric admissions since 1971, and all outpatientcontacts in psychiatric departments in Denmark since 1995.PATIENTS: All children between 2 and 10 years old who were diagnosed with autism during the period from 1971-2000.OUTCOME MEASURES: Annual and age-specific incidence for first day of first recorded admission with a diagnosis of autism in children between 2 and10 years old.RESULTS: A total of 956 children with a male-to-female ratio of 3.5:1 had been diagnosed with autism during the period from 1971-2000. There was notrend toward an increase in the incidence of autism during that period when thimerosal was used in Denmark, up through 1990. From 1991 until 2000 theincidence increased and continued to rise after the removal of thimerosal from vaccines, including increases among children born after thediscontinuation of thimerosal.CONCLUSIONS: The discontinuation of thimerosal-containing vaccines in Denmark in 1992 was followed by an increase in the incidence of autism. Ourecological data do not support a correlation between thimerosal-containing vaccines and the incidence of autism.•Stehr-Green P et al. Autism and thimerosal-containing vaccines: lack of consistent evidence for an association. Am J Prev Med. 2003, 25: 101-6In 1999, concerns were raised that vaccines containing the preservative Thimerosal might increase the risk of autism and/or other neurodevelopmentaldisorders.METHODS: Between the mid-1980s through the late-1990s, we compared the prevalence/incidence of autism in California, Sweden, and Denmark withaverage exposures to Thimerosal-containing vaccines. Graphic ecologic analyses were used to examine population-based data from the United States(national immunization coverage surveys and counts of children diagnosed with autism-like disorders seeking special education services in California);Sweden (national inpatient data on autism cases, national vaccination coverage levels, and information on use of all vaccines and vaccine-specificamounts of Thimerosal); and Denmark (national registry of inpatient/outpatient-diagnosed autism cases, national vaccination coverage levels, andinformation on use of all vaccines and vaccine-specific amounts of Thimerosal).RESULTS: In all three countries, the incidence and prevalence of autism-like disorders began to rise in the 1985-1989 period, and the rate of increaseaccelerated in the early 1990s. However, in contrast to the situation in the United States, where the average Thimerosal dose from vaccines increasedthroughout the 1990s, Thimerosal exposures from vaccines in both Sweden and Denmark-already low throughout the 1970s and 1980s-began todecrease in the late 1980s and were eliminated in the early 1990s.CONCLUSIONS: The body of existing data, including the ecologic data presented herein, is not consistent with the hypothesis that increased exposure toThimerosal-containing vaccines is responsible for the apparent increase in the rates of autism in young children being observed worldwide.
  • 72. Children and heavy metals WHO AND THIOMERSAL Global Advisory Committee on Vaccine Safety remains of the view that there is no evidence supporting any change in WHO’s recommendations for thiomersal-containing vaccines and the vaccination of low-birth-weight infants where indicated WHO Weekly Epidemiological Record, 2008 72Thiomersal - Extract from report of Global Advisory Committee on Vaccine Safety (GACVS) meeting of18-19 June 2008, published in the WHO Weekly Epidemiological Record on 8 August 2008. Availableat www.who.int/vaccine_safety/topics/thiomersal/Jun_2008/en/index.html – accessed 22 September2011.The Global Advisory Committee on Vaccine Safety considered the presentation of a recentlypublished pharmacokinetic study of mercury in premature and low-birth-weight infants who received abirth dose of hepatitis B vaccine containing thiomersal.6 The results suggest that exposure tothiomersal-containing vaccines does not result in accumulation of mercury in blood and that the bloodhalf-life (2.9–4.1 days) of intramuscular ethyl mercury from thiomersal in vaccines in infants issubstantially shorter than that of oral methyl mercury in adults. The study concluded that exposureguidelines based on oral methyl mercury may not be appropriate for use in assessing the risk ofthiomersal in vaccines at dosages consistent with standard vaccination regimens.The Global Advisory Committee on Vaccine Safety also considered the results of a study conductedin Italy that examined the neuropsychological performance 10 years after immunization in infancy withthiomersal-containing vaccines (Tozzi A., unpublished data, 2008). According to the results, higherthiomersal exposure through vaccines administered in the first year of life was significantly associatedwith lower scores on 2 neuropsychological outcomes (motor function, measured using the finger-tapping test, and language, measured using the Boston naming test). The differences in mean scoreswere very small, detected only in girls, of doubtful clinical relevance, and not consistent with resultsfrom other studies of ethyl mercury. The observed associations may reflect the effect of chance.On the basis of the presented data, Global Advisory Committee on Vaccine Safety remains of the viewthat there is no evidence supporting any change in WHO’s recommendations for thiomersal-containingvaccines and the vaccination of low-birth-weight infants where indicated.
  • 73. Children and heavy metals MERCURY IN BLOOD WAS SIMILAR IN PRESCHOOLERS WITH AUTISM COMPARED WITH UNAFFECTED CONTROLS Objectives: We compared blood total mercury in children with autism or autism spectrum disorder and typically developing controls in population-based samples, and determined the role of fish consumption in differences observed. Methods: Childhood autism risk from genetics and the environment study enrolled children 2-5 years of age. Analyzed 3 groups: autism spectrum disorder, non- autism spectrum disorder with developmental delay, and population-based typically developing controls. Multiple linear regression analysis was conducted (n = 452) to predict blood Hg from diagnostic status controlling for mercury sources. Hertz-Picciotto I et al, 2010 73Ref:•Hertz-Picciotto I et al. Blood mercury concentrations in CHARGE Study children with and without autism. EnvironHealth Perspect. 2010, 118(1):161-6.Some authors have reported higher blood mercury (Hg) levels in persons with autism, relative to unaffectedcontrols.OBJECTIVES: We compared blood total mercury concentrations in children with autism or autism spectrumdisorder (AU/ASD) and typically developing (TD) controls in population-based samples, and determined the role offish consumption in differences observed.METHODS: The Childhood Autism Risk from Genetics and the Environment (CHARGE) Study enrolled children 2-5 years of age. After diagnostic evaluation, we analyzed three groups: autism spectrum disorder (AU/ASD), non-autism spectrum disorder (non-AU/ASD) with developmental delay (DD), and population-based typicallydeveloping (TD) controls. Mothers were interviewed about household, medical, and dietary exposures. Blood Hgwas measured by inductively coupled plasma mass spectrometry. Multiple linear regression analysis wasconducted (n = 452) to predict blood Hg from diagnostic status controlling for Hg sources.RESULTS: Fish consumption strongly predicted total mercury (Hg) concentration. Autism spectrum disorder(AU/ASD) children ate less fish. After adjustment for fish and other Hg sources, blood Hg levels in autism spectrumdisorder (AU/ASD) children were similar to those of typically developing children (p = 0.75); this was also trueamong non-fish eaters (p = 0.73). The direct effect of autism spectrum disorder (AU/ASD) diagnosis on bloodmercury not through the indirect pathway of altered fish consumption was a 12% reduction. Developmental Delay(DD) children had lower blood Hg concentrations in all analyses. Dental amalgams in children with gum-chewing orteeth-grinding habits predicted higher levels.CONCLUSIONS: After accounting for dietary and other differences in Hg exposures, total Hg in blood was neitherelevated nor reduced in CHARGE Study preschoolers with autism spectrum disorder (AU/ASD) compared withunaffected controls, and resembled those of nationally representative samples.
  • 74. Children and heavy metals MERCURY IN BLOOD WAS SIMILAR IN PRESCHOOLERS WITH AUTISM COMPARED WITH UNAFFECTED CONTROLS Results Fish consumption strongly predicted total Hg concentration. After adjustment for fish and other mercury sources, blood Hg levels in autism spectrum disorder children were similar to those of typically developing controls children (p = 0.75). Developmental delay children had lower blood mercury in all analyses. Dental amalgams in children with gum-chewing or teeth-grinding habits predicted higher levels. Conclusions After accounting for dietary and other differences in mercury exposures, total mercury in blood was similar in the study preschoolers with autism spectrum disorder compared with unaffected controls, and resembled those of nationally representative samples. Hertz-Picciotto I et al, 2010 74Ref:•Hertz-Picciotto I et al. Blood mercury concentrations in CHARGE Study children with and withoutautism. Environ Health Perspect. 2010, 118(1):161-6.Some authors have reported higher blood mercury (Hg) levels in persons with autism, relative tounaffected controls.OBJECTIVES: We compared blood total mercury concentrations in children with autism or autismspectrum disorder (AU/ASD) and typically developing (TD) controls in population-based samples, anddetermined the role of fish consumption in differences observed.METHODS: The Childhood Autism Risk from Genetics and the Environment (CHARGE) Studyenrolled children 2-5 years of age. After diagnostic evaluation, we analyzed three groups: autismspectrum disorder (AU/ASD), non-autism spectrum disorder (non-AU/ASD) with developmental delay(DD), and population-based typically developing (TD) controls. Mothers were interviewed abouthousehold, medical, and dietary exposures. Blood Hg was measured by inductively coupled plasmamass spectrometry. Multiple linear regression analysis was conducted (n = 452) to predict blood Hgfrom diagnostic status controlling for Hg sources.RESULTS: Fish consumption strongly predicted total mercury (Hg) concentration. Autism spectrumdisorder (AU/ASD) children ate less fish. After adjustment for fish and other Hg sources, blood Hglevels in autism spectrum disorder (AU/ASD) children were similar to those of typically developingchildren (p = 0.75); this was also true among non-fish eaters (p = 0.73). The direct effect of autismspectrum disorder (AU/ASD) diagnosis on blood mercury not through the indirect pathway of alteredfish consumption was a 12% reduction. Developmental Delay (DD) children had lower blood Hgconcentrations in all analyses. Dental amalgams in children with gum-chewing or teeth-grinding habitspredicted higher levels.CONCLUSIONS: After accounting for dietary and other differences in Hg exposures, total Hg in bloodwas neither elevated nor reduced in CHARGE Study preschoolers with autism spectrum disorder(AU/ASD) compared with unaffected controls, and resembled those of nationally representativesamples.
  • 75. Children and heavy metals We hold our future in our hands and it is our children. Poster Contest by HRIDAY with support from WHO South East Asia Regional Office Asia 75We end with this beautiful reminder to us from a child in India, We must recognize the risksto our children and assume our responsibilities of preventing them, because we hold ourfuture in our hands—and it is our children.Thank you.
  • 76. Children and heavy metals ACKNOWLEDGEMENTSWHO is grateful to the US EPA Office of Children’s Health Protection for financial support thatmade this project possible and for some of the data, graphics and text used in preparing thesematerials for a broad audience. Further support was kindly provided by the UK Department of Health.First draft prepared by Yona Amitai, MD, MPH (Israel)With the advice of the Working Group Members on the Training Package for the Health Sector: Cristina Alonzo MD (Uruguay); Yona Amitai MD MPH (Israel); Stephan Boese-O’Reilly MD MPH (Germany); Stephania Borgo MD (ISDE, Italy); Irena Buka MD (Canada); Ernesto Burgio (ISDE, Italy); Lilian Corra MD (Argentina); Ligia Fruchtengarten MD (Brazil); Amalia Laborde MD (Uruguay); Jenny Pronczuk MD (WHO) Christian Schweizer TO (WHO/EURO); Kathy Shea MD (USA).Reviewers: Dr Huw Brunt (UK), Prof Gary Coleman (UK), Dr Raquel Duarte- Davidson (UK), Dr Elaine Lynch Farmery (UK), Alison M Good BSc Dip Med Tox MSc (UK), Dr Mark Griffiths (UK), Dr John Thompson (UK), Dr Laura Yates (UK)WHO Project coordination: Ruth A. Etzel, MD PhD Marie-Noël Bruné, MScLatest update: October 2011 76
  • 77. Children and heavy metals DISCLAIMERThe designations employed and the presentation of the material in this publication do not imply theexpression of any opinion whatsoever on the part of the World Health Organization concerning thelegal status of any country, territory, city or area or of its authorities, or concerning the delimitation ofits frontiers or boundaries. Dotted lines on maps represent approximate border lines for which theremay not yet be full agreement.The mention of specific companies or of certain manufacturers’ products does not imply that they areendorsed or recommended by the World Health Organization in preference to others of a similarnature that are not mentioned. Errors and omissions excepted, the names of proprietary products aredistinguished by initial capital letters.The opinions and conclusions expressed do not necessarily represent the official position of theWorld Health Organization.This publication is being distributed without warranty of any kind, either express or implied. In noevent shall the World Health Organization be liable for damages, including any general, special,incidental, or consequential damages, arising out of the use of this publicationThe contents of this training module are based upon references available in the published literatureas of its last update. Users are encouraged to search standard medical databases for updates in thescience for issues of particular interest or sensitivity in their regions and areas of specific concern.If users of this training module should find it necessary to make any modifications (abridgement,addition or deletion) to the presentation, the adaptor shall be responsible for all modifications made.The World Health Organization disclaims all responsibility for adaptations made by others. Allmodifications shall be clearly distinguished from the original WHO material. 77